Bifluorodioxalane-amino-benzimidazole kinase inhibitors for the treatment of cancer, autoimmuneinflammation and cns disorders

ABSTRACT

The invention relates to a compound of the general formula (I) or a physiologically functional derivative, solvate or salt thereof, 
     
       
         
         
             
             
         
       
     
     wherein 
     A is a bond, alkyl or alkoxy optionally substituted with one or more R″ as defined herein, *—N(R′″)CO—, *—CON(R′″)—, *—N(R′″)CON(R′″)—, —S—, —SO—, *—N(R′″)—, *—N(R′″)CO—, *—CON(R′″)—, —CO—, *—COO—, *—OOC—, *—SO 2 N(R′″)—, —SO 2 , or *—N(R′″)—SO 2 —, wherein R′″ is as defined herein and * specifies the point of attachment to X; X is aryl, cycloalkyl, aralkyl, heterocyclyl or heteroaryl, which may be substituted with one or more R X  further described herein; L is a bond or *—N(R N )CO—, *—CON(R N )—, *—N(R N )—, *—C═N(R N )—, *—N(R N )-alkyl-, *-alkyl-N(R N )—, *—N(R N )CON(R N )—, *—CO—, *—CO 2 —, alkyl, *-alkyl-O-alkyl-, *—NCO—CH═CH—, *—CH═CH—CONH—, *—SO 2 N(R N )—, *—N(R N )SO 2 —, or heterocyclyl, wherein * specifies the point of attachment to X; Y is H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl or heteroaryl, which may be substituted with one or more R Y  further described herein; and R and R N  are further described herein; as well as their use as a medicament, a pharmaceutical composition comprising them, a method of treatment or prevention of a medical condition entailing the administration thereof, and the use thereof in the manufacture of a medicament for the treatment or prevention of a medical condition, particularly autoimmune inflammatory disorders, CNS disorders, sleeping disorders, or proliferative diseases including cancer. The invention further relates to a specific process for the preparation of said compounds.

BACKGROUND OF THE INVENTION

Casein kinase 1 (CK1) is a family of highly related, constitutivelyactive serine/threonine protein kinases (Christenson E, De Maggio A Jand Hockstra M F. (1997). Recent Results Cancer Res. 143, 263-274.;Gross S D and Anderson R A. (1998). Cell Signal 10, 699-711).

CK1 is ubiquitously expressed in eukaryotes. Mammalian family memberscomprise at least seven mammalian CK1 isoforms (α, β, γ1, γ2, γ3, δ andδ) and their various splice variants. (Fish K J, Cegielska A, Getman ME, Landes G M and Virshup D M. (1995). J. Biol. Chem. 270, 14875-14883.;Graves P R, Haas D W, Hagedorn C H, De Paoli-Roach A A and Roach P J.(1993). J. Biol. Chem. 268, 6394-6401.; Rowles J, Slaughter C, Moomaw C,Hsu J and Cobb M H. (1991). Proc. Natl. Acad. Sci. USA 88, 9548-9552.;Zhai L, Graves P R, Robinson L C, Italiano M, Culbertson M R, Rowles J,Cobb M H, De Paoli-Roach A A and Roach P J. (1995). J. Biol. Chem. 270,12717-12724).

These isoforms share a high degree of similarity within their proteinkinase domains. For example CK1δ and CK1ε are 98% identical in thisregion (Fish K J, Cegielska A, Getman M E, Landes G M and Virshup D M.(1995). J. Biol. Chem. 270, 14875-14883.; Graves P R, Haas D W, HagedornC H, De Paoli-Roach A A and Roach P J. (1993). J. Biol. Chem. 268,6394-6401), but show considerable variation in the presence, length andprimary structure of the C-terminal non-catalytic domain (Christenson E,De Maggio A J and Hockstra M F. (1997). Recent Results Cancer Res. 143,263-274). These variable C-terminal domains are responsible forsubstrate specificity of the different isoforms (Cegielska A, Gietzen KF, Rivers A and Virshup D M. (1998). J. Biol. Chem. 273, 1357-1364.;Graves P R and Roach P J. (1995). J. Bio. Chem. 270, 21689-21694.) andare involved in the regulation of the interaction with other proteins,and/or subcellular structures.

Autophosphorylation, (Cegielska A, Gietzen K F, Rivers A and Virshup DM. (1998). J. Biol. Chem. 273, 1357-1364; and perhaps dimerization inthe case of CK1δ Longenecker K L, Roach P J and Hurley T D. (1998). ActaCrystallogr. D. Biol. Crystallogr. 54, 473-475) are additionalmechanisms that regulate CK1 activity, specificity, and sub-cellularlocalization. The list of known substrates of the CK1 family is stillincreasing, and so far includes cytoskeleton proteins such as spectrin,troponin, myosin and tau (Simkowski K W and Tao M. (1980) J. Biol. Chem.255, 6456-6461; Singh T J, Akatsuka A, Blake K R and Huang K P. (1983).Arch. Biochem. Biophys. 220, 615-622.; Singh T J, Grunke-Iqbal I andIqbal K. (1995). J. Neurochem. 64, 1420-1423; and transcriptionalcomponents such as RNA polymerases I and II, SV40 T antigen and CREMDahmus M E. (1981). J. Biol. Chem. 256, 11239-11243.; de Groot R P, denHertog J, Vandenhee de J R, Grois J and Sassone-Corsi P. (1993). EMBO J,12, 3903-3911.; Grasser F A, Scheidtmann K H, Tuazon P T, Traugh J A andWalter G. (1988). Virology 165, 13-22).

CK1 isoforms can influence the development of tumors in many ways. Theirability to modulate p53 and Mdm2 functions through site-directedphosphorylation, their function in centrosome and spindle regulation,the opposite roles of CK1 isoforms in Wnt signaling and theirinvolvement in impeding apoptosis demonstrate the potential role of CK1family members in proliferative diseases on multiple levels. Differentisoforms seem to play an important role in the development andprogression of certain tumor types. Therefore, the interest in targetingCK1 for drug development has increased within the last 5 years. The roleof the casein kinase 1 (CK1) family in different signaling pathways islinked to cancer development (Uwe Knippschild et. al., Onkologie 2005;28:508-514). Further information on specific disorders connected withthe casein kinase 1 (CK1) family has been published in: Uwe Knippschildet al., Cellular Signalling 17 (2005) 675-689.

The Wnt and Hedgehog pathways are involved in the regulation of stemcell identity and the initiation and maintenance of many tumor types.Dysregulation of these pathways play an important role in cancer stemcell maintainence. Casein kinases 1ε and 1δ are mainly positivemodulators of the Wnt and the Hh pathways. Thus, selective inhibition ofCasein kinases 1ε and 1δ inhibit the proliferation and self renewal ofcancer stem cells.

Multiple members of the casein kinase I family of serine/threonineprotein kinases can have positive or negative effects on individualregulatory elements of the Wnt and Hedgehog pathway, which in summaryleads to inhibition. These roles, including recent results on Caseinkinase 1 (CK1) phosphorylation and activation of LRP6, CKIphosphorylation of Ci and mediation of Ci-Slimb/β-TrCP binding wererevieved (“CKI, There's more than one: casein kinase I family members inWnt and Hedgehog signaling” Price M A, Genes & Dev. 2006. 20: 399-410).Both the Wnt and Hh signaling pathways are important in manydevelopmental patterning events.

Alzheimer's desease is an age-related disorder characterized in part bythe appearance of intracellular lesions composed of filamentousaggregates of the microtubule-assiciated protein tau. Abnormal tauphosphorylation accompanies tau aggregation and is considered to be anupstream pathological event in this desease. Enzymes implicated in tauhyperphosphorylation in Alzheimer's desease include members of thecasein kinase 1 family. (Kannanayakal, T J et al. Nuerosci Lett. 2008;432(2): 141-5.)

The circadian clock links our daily cycles of sleep and activity to theexternal environment. Deregulation of the clock is implicated in anumber of human disorders, including depression, seasonal affectivedisorder and metabolic disorders. Casein kinase 1 epsilon (CK1ε) andcasein kinase 1 delta (CK1δ) are Ser-Thr protein kinases, which areclosely related to each other and serve as key clock regulators. Thiswas demonstrated by mutations in CK1δ and CK1ε that dramatically alterthe circadian period. Therefore, inhibitors of CK1 have utility intreating circadian disorders. (Walten, K. M. et al. JPET 330:430-439,2009.)

Several publications describe casein kinase inhibitors: Wager Travis et.al. Abstracts of Papers, 238^(th) ACS National Meeting, Washington,D.C., United States, Aug. 16-20, 2009; Oumata Nassima et al. Journal ofMedicinal Chemistry Volume 51 Issue 17 Pages 5229-5242 Journal 2008;Mashhoon N. et al. J Biol Chem 200; 275(26): 20052-60; Pfeifer C. et al.J Med Chem. 2009 Dec. 10; 52(23):7618-30.

In addition several patent applications regarding CK1δ and/or εinhibitors were published: US 2010/0179154 A1; US 2004/0110808 A1; US2008/0027124 A1; US 2009/0099237 A1.

Several patents and patent applications described certain specificacyl-amino-benzimidazoles with pharmacological activity: EP 1 388 341 A1and US 2004/0110808 A1; U.S. Pat. No. 7,132,438 B2; WO 2007/064932 A2;DE 27 54 930 Al; US 2003/0144286.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula (I),and in further embodiments compounds of Formula (Ia), and theirrespective physiologically functional derivatives or salts, where thegroups A, X, L, and Y are detailed further herein below.

In another aspect, the present invention provides methods forpreparation of compounds of Formulae (I) or (Ia), physiologicallyfunctional derivatives or salts thereof, as detailed further hereinbelow.

In another aspect, the present invention provides methods for thetreatment or prevention of certain medical conditions, the methodcomprising the administration of compounds of Formulae (I) or (Ia),physiologically functional derivatives or salts thereof, to a subject inneed thereof, as detailed further herein below.

In another aspect, the present invention provides the use of compoundsof Formulae (I) or (Ia), physiologically functional derivatives or saltsthereof, in the manufacture of a medicament for the treatment orprevention of certain medical conditions, as detailed further hereinbelow.

In another aspect, the present invention provides compounds of Formulae(I) or (Ia), physiologically functional derivatives or salts thereof,for use in the treatment or prevention of certain medical conditions, asdetailed further herein below.

In another aspect, the present invention provides pharmaceuticalcompositions comprising compounds of Formulae (I) or (Ia),physiologically functional derivatives or salts thereof and one or morepharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the inhibition of anchorage independent growth of coloniesof the pancreatic cancer cell line PANC1 by the compound of Example 1(columns marked as“A”), compared with DMSO as control. a) The compoundof Example 1 reduces anchorage independent growth of PANC1 colonies. b)The compound of Example 1 is particularly potent in the inhibition ofPANC1 macrocolonies, which represent a subpopulation the colonies of a).

DETAILED DESCRIPTION OF THE INVENTION

Described herein is a compound of the general formula (I) or aphysiologically functional derivative, solvate or salt thereof,

wherein

R is independently selected from the group comprising H, halogen, alkyl,haloalkyl, haloalkoxy, OH, alkoxy, aryl, heteroaryl, cycloalkyl,heterocyclyl, —S—R′″, —SO—R′″, nitro, —NH₂, —N(R′″)₂, —NH(R′″),—NHCO(R′″), —CONH₂, —CONH(R′″), —CO(R′″), —COH, —COO(R′″), —COOH,—SO₂NH₂, —SO₂NH(R′″), —SO₂(R′″), —NH—SO₂(R′″), and —CNCOOR′″, wherein inthe cases where said group R is alkyl, haloalkyl, haloalkoxy, alkoxy,aryl, heteroaryl, cycloalkyl, or heterocyclyl, said group R may besubstituted with one or more substituents R″ independently selected fromthe group comprising H, halogen, alkyl, haloalkyl, haloalkoxy, OH,alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, —S-alkyl,—S-haloalkyl, nitro, —NH₂, —N(alkyl)₂, —NH(alkyl), —NHCO(alkyl), —CONH₂,—CONH(alkyl), —CO(alkyl), —COH, —COO(alkyl), —COOH, —SO₂NH₂,—SO₂NH(alkyl), —SO₂(alkyl), —NH—SO₂(alkyl), and —CN, and wherein R′″ isindependently selected from the group comprising H, alkyl, haloalkyl,aryl, heteroaryl, cycloalkyl and heterocyclyl;

R^(N) is independently selected from the group comprising H, alkyl,haloalkyl, OH, aryl, heteroaryl, cycloalkyl, heterocyclyl, —SO—R′″,—NH₂, —N(R′″)₂, —NH(R′″), —NHCO(R′″), —CONH₂, —CONH(R′″), —CO(R′″),—COH, —COO(R′″), —COOH, —SO₂NH₂, —SO₂NH(R′″), —SO₂(R′″), and—NH—SO₂(R′″), wherein in the cases where said group R^(N) is alkyl,haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, said groupR^(N) may be substituted with one or more substituents R′″ as definedabove, and wherein R′″ is as defined above;

A is independently selected from the group comprising a bond, alkyloptionally substituted with one or more substituents R″ as definedabove, alkoxy optionally substituted with one or more substituents R″ asdefined above, *—N(R′″)CO—, *—CON(R′″)—, *—N(R′″)CON(R′″)—, —S—, —SO—,*—N(R′″)—, *—N(R′″)CO—, *—CON(R′″)—, —CO—, *—COO—, *—OOC—, *—SO₂N(R′″)—,—SO₂, and *—N(R′″)—SO₂—, wherein R′″ is as defined above and wherein *specifies the point of attachment to X;

X is independently selected from the group comprising aryl, cycloalkyl,aralkyl, heterocyclyl and heteroaryl, wherein said group X may besubstituted with one or more R^(X) independently selected from the groupcomprising halogen, alkyl, haloalkyl, haloalkoxy, OH, alkoxy, aryl,heteroaryl, cycloalkyl, heterocyclyl, —S—(R′″), nitro, —NH₂, —N(R′″)₂,—NH(R′″), —NHCO(R′″), —CONH₂, —CONH(R′″), —CO(R′″), —COH, —COO(R′″),—COOH, —SO₂NH₂, —SO₂NH(R′″), —SO₂(R′″), —NH—SO₂(R′″), cycloalkyl, and—CN, and wherein R′″ is as defined above;

L is independently a bond or a linker group selected from the groupcomprising *—N(R^(N))CO—, *—CON(R^(N))—, *—N(R^(N))—, *—C═N(R^(N))—,*—N(R^(N))-alkyl-, *-alkyl-N(R^(N))—, *—N(R^(N))CON(R^(N))—, *—CO—,*—SO₂—, alkyl, *-alkyl-O-alkyl-, *—NCO—CH═CH—, *—CH═CH—CONH—,*—SO₂N(R^(N))—, *—N(R^(N))SO₂—, and heterocyclyl, wherein * specifiesthe point of attachment to X; and wherein R^(N) is as defined above;

and wherein

Y is independently selected from the group comprising H, alkyl, aryl,aralkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein said group Ymay optionally be substituted with one or more R^(Y) independentlyselected from the group comprising halogen, alkyl, haloalkyl,haloalkoxy, OH, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl,—S—(R′″), nitro, —NH₂, —N(R′″)₂, —NH(R′″), —NHCO(R′″), —CONH₂,—CONH(R′″), —CO(R′″), —COH, —COO(R′″), —COOH, —SO₂NH₂, —SO₂NH(R′″),—SO₂(R′″), —NH—SO₂(R′″), cycloalkyl, and —CN, and wherein R′″ is asdefined above.

Embodiments of the present invention are enumerated in the following:

1. A compound of the general formula (I) or a physiologically functionalderivative, solvate or salt thereof,

wherein

R is independently selected from the group comprising H, halogen,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, —S—R′″,—SO—R′, nitro, —N(R′″)₂, —NH(R′″), —NHCO(R′″), —CONH₂, —CONH(R′″),—CO(R′″), —COH, —COO(R′″), —COOH, —SO₂NH₂, —SO₂NH(R′″), —SO₂(R′″), and—NH—SO₂(R′″),

wherein in the cases where said group R is C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, or C₁₋₆-alkoxy, said group R may be substituted withone or more substituents R″ independently selected from the groupcomprising H, halogen, OH, nitro, —NH₂, —N(C₁₋₆-alkyl)₂,—NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl),—CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH, and —CN,

and wherein R′″ is independently selected from the group comprising H,C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl;

R^(N) is independently selected from the group comprising H, alkyl,haloalkyl, OH, aryl, heteroaryl, cycloalkyl, heterocyclyl, —SO—R′″,—NH₂, —N(R′″)₂, —NH(R′″), —NHCO(R′″), —CONH₂, —CONH(R′″), —CO(R′″),—COH, —COO(R′″), —COOH, —SO₂NH₂, —SO₂NH(R′″), —SO₂(R′″), and—NH—SO₂(R′″), wherein R′″ is as defined above,

wherein in the cases where said group R^(N) is alkyl, haloalkyl, aryl,heteroaryl, cycloalkyl, or heterocyclyl, said group R^(N) may besubstituted with one or more substituents R′″ as defined above;

A is independently selected from *—N(R^(a))CO—, *—CON(R^(a))—,*—SO₂N(R^(a))—, and *—N(R^(a))—SO₂—,

wherein R¹ is selected from H and C₁₋₄-alkyl,

and wherein * specifies the point of attachment to X; X is independentlyselected from the group comprising aryl, cycloalkyl, aralkyl,heterocyclyl and heteroaryl, wherein said group X may be substitutedwith one or more R^(X) independently selected from the group comprisinghalogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy,aryl, heteroaryl, cycloalkyl, heterocyclyl, —S—C₁₋₆-haloalkyl,—S—C₁₋₆-haloalkyl, nitro, —NH₂, —N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl),—NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH,—COO(C₁₋₆-alkyl), —COOH, —SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl),—NH—SO₂(C₁₋₆-alkyl), C₃₋₆-cycloalkyl, and —CN;

L is independently a bond or a linker group selected from the groupcomprising *—NHCO—, *—CONH—, *—NH—, *—N(C₁₋₄-alkyl)-,*—C═N(C₁₋₄-alkyl)-, *—NH—C₁₋₄-alkyl-, *—C₁₋₄-alkyl-NH—, *—NHCONH—,*—CO—, *—SO₂—, C₁₋₂-alkyl-O—C₁₋₂-alkyl-, *—NHCO—CH═CH—, *—CH═CH—CONH—,*—SO₂NH—, *—NHSO₂—, and pyridinyl, wherein * specifies the point ofattachment to X; and

Y is independently selected from the group comprising H, alkyl, aryl,aralkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein said group Ymay optionally be substituted with one or more R^(Y) independentlyselected from the group comprising halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, aryl, heteroaryl, cycloalkyl,heterocyclyl, —S—C₁₋₆-alkyl, —S—C₁₋₆-haloalkyl, nitro, —NH₂,—N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂,—CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH,—SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), —NH—SO₂(C₁₋₆-alkyl),C₁₋₆-alkyl-heterocyclyl, cycloalkyl and —CN.

2. A compound according to the present invention, in particularaccording to above item 1, which is a compound of the general formula(Ia) or a physiologically functional derivative, solvate or saltthereof,

wherein

X is independently selected from the group comprising aryl, cycloalkyl,aralkyl, heterocyclyl and heteroaryl, wherein said group X may besubstituted with one or more R^(X) independently selected from the groupcomprising halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH,C₁₋₆-alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, —S—C₁₋₆-alkyl,—S—C₁₋₆-haloalkyl, nitro, —NH₂, —N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl),—NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH,—COO(C₁₋₆-alkyl), —COOH, —SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl),—NH—SO₂(C₁₋₆-alkyl), C₃₋₆-cycloalkyl, and —CN;

L is independently a bond or a linker group selected from the groupcomprising *—NHCO—, *—CONH—, *—NH—, *—N(C₁₋₄-alkyl)-,*—C═N(C₁₋₄-alkyl)-, *—NH—C₁₋₄-alkyl-, *—C₁₋₄-alkyl-NH—, *—NHCONH—,*—CO—, *—SO₂—, C₁₋₄-alkyl, *—C₁₋₂-alkyl-O—C₁₋₂-alkyl-, *—NHCO—CH═CH—,*—CH═CH—CONH—, *—SO₂NH—, *—NHSO₂—, and pyridinyl, wherein * specifiesthe point of attachment to X; and

Y is independently selected from the group comprising H, alkyl, aryl,aralkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein said group Ymay optionally be substituted with one or more R^(Y) independentlyselected from the group comprising halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, aryl, heteroaryl, cycloalkyl,heterocyclyl, —S—C₁₋₆-alkyl, —S—C₁₋₆-haloalkyl, nitro, —NH₂,—N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂,—CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH,—SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), —NH—SO₂(C₁₋₆-alkyl),C₁₋₆-alkyl-heterocyclyl, cycloalkyl and -CN.

3. The compound according to the present invention, in particularaccording to above item 1 or 2 or a physiologically functionalderivative, solvate or salt thereof, wherein

X is independently selected from the group comprising aryl, cycloalkyl,heterocyclyl and heteroaryl, wherein said group X may be substitutedwith one or more R^(X) independently selected from the group comprisingF, Cl, Br, I, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH,C₁₋₆-alkoxy, nitro, —NH₂, —N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl),—NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl), —SO₂NH₂,—SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), C₃₋₆-cycloalkyl,—NH—SO₂(C₁₋₆-alkyl), —COO—C₁₋₆-alkyl, and —CN;

L is independently a bond or a linker group selected from the groupcomprising *—NHCO—, *—NH—, *—NHCH₂—, *—NHCONH—, *—NHCO—CH═CH—, *—NHSO₂—,*—SO₂—, and pyridinyl, wherein * specifies the point of attachment to X;and

Y is independently selected from the group comprising H, aryl,cycloalkyl, heterocyclyl and heteroaryl, wherein said group Y mayoptionally be substituted with one or more R^(Y) independently selectedfrom the group comprising F, Cl, Br, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, C₁₋₆-alkoxy, C₁₋₆-alkyl-morpholinyl, and nitro.

4. The compound according to the present invention, in particularaccording to any of the above items 1 to 3 or a physiologicallyfunctional derivative, solvate or salt thereof, wherein

X is independently selected from the group comprising aryl, aralkyl,cycloalkyl, heterocyclyl and heteroaryl, wherein said group X may besubstituted with one or more R^(X) independently selected from the groupcomprising F, Cl, Br, I, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy,OH, C₁₋₆-alkoxy, nitro, —NH₂, —N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl),—NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl), —SO₂NH₂,—SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), C₃₋₆-cycloalkyl,—NH—SO₂(C₁₋₆-alkyl), —COO—C₁₋₆-alkyl, —COOH, and —CN;

L is independently a bond or a linker group selected from the groupcomprising *—NHCO—, *—NH—, *—NHCH₂—, *—NHCONH—, *—NHCO—CH═CH—, *—NHSO₂—,*—SO₂—, and pyridinyl, wherein * specifies the point of attachment to X;and

Y is independently selected from the group comprising H, aryl,cycloalkyl, heterocyclyl and heteroaryl, wherein said group Y mayoptionally be substituted with one or more R^(Y) independently selectedfrom the group comprising F, Cl, Br, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, C₁₋₆-alkoxy, C₁₋₆-alkyl-morpholinyl, and nitro.

5. The compound according to the present invention, in particularaccording to any of the above items 1 to 4 or a physiologicallyfunctional derivative, solvate or salt thereof, wherein

X is independently selected from the group comprising1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl,1H-1,2,4-triazolyl, 1H-pyrazolyl, 1H-pyrrolyl, phenyl,benzo[b]thiophenyl, cyclohexyl, furyl, isoxazolyl, oxazolyl, imidazolyl,1H-pyrazolyl, pyrazinyl, pyridyl, quinolinyl, 1-(naphthalen-2-yl)ethyl,thiazolyl and thiophenyl, wherein said group X may be substituted withone or more R^(X) independently selected from the group comprising F,Cl, Br, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy,difluoromethoxy, OH, acetyl, methylcarbamoyl, methoxy, nitro, —NH₂,—NEt₂, —NMe₂, —NHEt, —NHCOCH₃, —CONH₂, —SO₂NH₂, —SO₂Me, —NH—SO₂Me, and—CN;

L is independently a bond or a linker group selected from the groupcomprising comprising *—NHCO—, *—NH—, *—NHCH₂—, *—NHCONH—,*—NHCO—CH═CH—, *-pyridinyl-, —SO₂—, and *—NHSO₂—, wherein * specifiesthe point of attachment to X; and

Y is independently selected from the group comprising H, phenyl, furyl,thiophenyl, pyridyl, pyrimidyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl,thieno[3,2-d]pyrimidinyl, 2-oxo-2,3-dihydrobenzoimidazolyl,pyrrolidinyl, tetrazolyl, piperidinyl, pyrazolyl, 1,2,4-oxadiazolyl,1,2,3-thiadiazolyl, pyrrolyl, imidazolyl, isoxazolyl, thiazolyl, andmorpholinyl, wherein said group Y may be substituted with one or twoR^(Y) independently selected from the group comprising F, Cl, methyl,isopropyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy,methylcarbamoyl, cyclopropyl, 2-morpholinoethyl, and nitro.

6. The compound according to the present invention, in particularaccording to any of the above items 1 to 5 or a physiologicallyfunctional derivative, solvate or salt thereof, wherein

X is independently selected from the group comprising1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl,1H-1,2,4-triazolyl, 1H-pyrazolyl, 1H-pyrrolyl, phenyl,benzo[b]thiophenyl, cyclohexyl, furyl, isoxazolyl, oxazolyl, imidazolyl,1H-pyrazolyl, pyrazinyl, pyridyl, quinolinyl, 1-(naphthalen-2-yl)ethyl,thiazolyl, benzyl and thiophenyl, wherein said group X may besubstituted with one or more R^(X) independently selected from the groupcomprising F, Cl, Br, methyl, tert-butyl, trifluoromethyl,trifluoromethoxy, difluoromethoxy, OH, acetyl, methylcarbamoyl, methoxy,nitro, —NH₂, —NEt₂, —NMe₂, —NHEt, —NHCOCH₃, —CONH₂, —SO₂NH₂, —SO₂Me,—NH—SO₂Me, —COOH, and —CN;

L is independently a bond or a linker group selected from the groupcomprising comprising *—NHCO—, *—NH—, *—NHCH₂—, *—NHCONH—,*—NHCO—CH═CH—, *-pyridinyl-, —SO₂—, and *—NHSO₂—, wherein * specifiesthe point of attachment to X; and

Y is independently selected from the group comprising H, phenyl, furyl,thiophenyl, pyridyl, pyrimidyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl,thieno[3,2-d]pyrimidinyl, 2-oxo-2,3-dihydrobenzoimidazolyl,pyrrolidinyl, tetrazolyl, piperidinyl, pyrazolyl, 1,2,4-oxadiazolyl,1,2,3-thiadiazolyl, pyrrolyl, imidazolyl, isoxazolyl, thiazolyl,thiomorpholinyl, and morpholinyl, wherein said group Y may besubstituted with one or two R^(Y) independently selected from the groupcomprising F, Cl, methyl, isopropyl, tert-butyl, trifluoromethyl,trifluoromethoxy, methoxy, methylcarbamoyl, cyclopropyl,2-morpholinoethyl, and nitro.

7. The compound according to the present invention, in particularaccording to any of the above items 1 to 6 or a physiologicallyfunctional derivative, solvate or salt thereof, wherein

X is independently selected from the group comprising

wherein * specifies the point of attachment to the central moiety, #specifies the point of attachment to L and wherein the group X may besubstituted with one or more R^(X);

L is independently a bond or a linker group selected from the groupcomprising *—NHCO—, *—NH—, *—NHCH₂—, *—NHCONH—, *—NHCO—CH═CH—,*-pyridinyl-, —SO₂—, and *—NHSO₂—, wherein * specifies the point ofattachment to X;

Y is independently H or selected from the group comprising

wherein * specifies the point of attachment to L and wherein the group Ymay be substituted with one or more R^(Y); or

wherein X is selected from the group comprising

wherein * specifies the point of attachment to the central moiety,wherein L is a bond, Y is H, and wherein the group X may be substitutedwith one or more R^(X);

wherein each R^(Y) is independently selected from the group comprisingF, Cl, methyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethoxy,methoxy, methylcarbamoyl, cyclopropyl, 2-morpholinoethyl, and nitro; and

wherein each R^(X) is independently selected from the group comprisingF, Cl, Br, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy,difluoromethoxy, OH, acetyl, methylcarbamoyl, methoxy, nitro, —NH₂,—NEt₂, —NMe₂, —NHEt, —NHCOCH₃, —CONH₂, —SO₂NH₂, —SO₂Me, —NH—SO₂Me, and—CN.

8. The compound according to the present invention, in particularaccording to any of the above items 1 to 7 or a physiologicallyfunctional derivative, solvate or salt thereof, wherein

X is independently selected from the group comprising

wherein * specifies the point of attachment to the central moiety, #specifies the point of attachment to L and wherein the group X may besubstituted with one or more R^(X);

L is independently a bond or a linker group selected from the groupcomprising *—NHCO—, *—NH—, *—NHCH₂—, *—NHCONH—, *—NHCO—CH═CH—,*-pyridinyl-, —SO₂—, and *—NHSO₂—, wherein * specifies the point ofattachment to X;

Y is independently H or selected from the group comprising

wherein * specifies the point of attachment to L and wherein the group Ymay be substituted with one or more R^(Y); or

wherein X is selected from the group comprising

wherein * specifies the point of attachment to the central moiety,wherein L is a bond, Y is H, and wherein the group X may be substitutedwith one or more R^(X);

wherein each R^(Y) is independently selected from the group comprisingF, Cl, methyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethoxy,methoxy, methylcarbamoyl, cyclopropyl, 2-morpholinoethyl, and nitro; and

wherein each R^(X) is independently selected from the group comprisingF, Cl, Br, methyl, tert-butyl, trifluoromethyl, trifluoromethoxy,difluoromethoxy, OH, acetyl, methylcarbamoyl, methoxy, nitro, —NH₂,—NEt₂, —NMe₂, —NHEt, —NHCOCH₃, —CONH₂, —SO₂NH₂, —SO₂Me, —NH—SO₂Me, —COOHand —CN.

In certain embodiments of the present invention, Y is a phenyl groupoptionally substituted with one or more R^(Y) as defined herein, moreparticularly a phenyl group substituted with one or more R^(Y) asdefined herein, wherein at least one of the substituents R^(Y) islocated in the meta of the phenyl group position, wherein the orthopositions of the phenyl group are H, and wherein said ortho and metapositions are in relation to the point of attachment to L, or in thecase where L is a bond, the point of attachment to X, respectively.

In certain embodiments of the present invention, R^(X) is in eachoccurrence independently selected from the group comprising alkyl,alkylsulfonyl, halogen, haloalkyl, hydroxy, amino, alkylamino,dialkylamino, benzylamino, nitro, alkoxy, haloalkoxy and cyano, moreparticularly selected from the group comprising methyl, methylsulfonyl,fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, amino,dimethylamino, ethylamino, diethylamino, benzylamino, nitro, methoxy,trifluoromethoxy and cyano.

In certain embodiments of the present invention, L independently is abond or selected from the group comprising *—NHCO—, *—NH SO₂—, *—SO₂—,*—CONH—, *—NH—, —NHCONH—, and *—SO₂NH—, particularly *—NHCO—, *—NH,*—NHCONH—, and *—NHSO₂—, wherein * specifies the point of attachment toX. More particularly, L independently is *—NHCO, wherein * specifies thepoint of attachment to X.

In certain embodiments of the present invention, R^(Y) is in eachoccurrence independently selected from the group comprising alkyl,halogen, haloalkyl, alkoxy, haloalkoxy and nitro, more particularlyselected from the group comprising methyl, chlorine, fluorine, methoxy,trifluoromethoxy and nitro.

Particular compounds of the present invention are those having an IC₅₀on cancer cell growth inhibition of 1 μM or lower, more particularly 100nM or lower. Said IC₅₀ is particularly determined as described hereinbelow in the exemplary section (under “9. Determination of proliferationinhibition on a panel of cancer cell lines; Proliferation Assay”), andparticular cancer types in this context are the ones described therein.

Furthermore, particular compounds of the present invention are thosehaving an IC₅₀ on CK1 delta and/or epsilon inhibition of 1 μM or lower,even more particularly 200 nM or lower. Said IC₅₀ is particularlydetermined as described herein below in the exemplary section (under “8.Determination of the inhibitory capacity; Kinase Assay”—Data shown intables 1 and 2).

9. The compound according to the present invention, in particularaccording to any of the above items 1 to 8, wherein said compound isselected from one of the compounds 1 to 149 enumerated in the examplesection, or a physiologically functional derivative, solvate or saltthereof.

10. The compound according to the present invention, in particularaccording to any of the above items 1 to 9, wherein said compound isselected from one of the compounds 1 to 149 or 1B to 26B enumerated inthe example section, or a physiologically functional derivative, solvateor salt thereof.

11. The compound according to the present invention, in particularaccording to any of the above items 1 to 10, wherein said compound isselected from one of the following compounds as enumerated in theexample section: 1, 2, 3, 11, 17, 18, 19, 20, 21, 26, 29, 30, 31, 33,37, 38, 41, 48, 49, 51, 52, 56, 57, 60, 62, 65, 66, 69, 70, 75, 76, 77,78, 80, 81, 82, 83, 87, 88, 91, 92, 94, 100, 101, 102, 104, 105, 108,111, 112, 113, 114, 116, 117, 118, 121, 122, 123, 124, 125, 126, 128,130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144,147, 148, and 149,

or a physiologically functional derivative, solvate or salt thereof.

12. The compound according to the present invention, in particularaccording to any of the above items 1 to 11, wherein said compound isselected from one of the following compounds as enumerated in theexample section: 1, 2, 3, 11, 17, 18, 19, 20, 21, 26, 29, 30, 31, 33,37, 38, 41, 48, 49, 51, 52, 56, 57, 60, 62, 65, 66, 69, 70, 75, 76, 77,78, 80, 81, 82, 83, 87, 88, 91, 92, 94, 100, 101, 102, 104, 105, 108,111, 112, 113, 114, 116, 117, 118, 121, 122, 123, 124, 125, 126, 128,130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144,147, 148, and 149, 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B,13B, 14B, 15B, 16B, 17B, 22B, 23B, and 25B.

or a physiologically functional derivative, solvate or salt thereof.

13. The compound according to the present invention, in particularaccording to any of the above items 1 to 12 or a physiologicallyfunctional derivative, solvate or salt thereof for use as a medicament.

14. The compound according to the present invention, in particularaccording to any of the above items 1 to 12 or a physiologicallyfunctional derivative, solvate or salt thereof for use in the treatmentor prevention of a medical condition selected from the group comprisingautoimmuneinflammatory disorders, more particularly selected from thegroup comprising inflammatory Bowel disease, multiple sclerosis,rheumathoid arthritis, autoimmune uveitis, CNS disorders, particularlyselected from the group comprising Alzheimer's desease, Parkinson'sdesease, Down's syndrom, sleeping disorders, particularly sleepingdisorders in connection with the circadian clock mechanism, andproliferative diseases including cancer.

15. A pharmaceutical composition comprising a compound according to thepresent invention, in particular according to any of the above items 1to 12 or a physiologically functional derivative, solvate or saltthereof and one or more pharmaceutically acceptable excipients.

Furthermore, the present invention relates to a method of treatment orprevention of the medical conditions specified herein, which comprisesthe administration of an effective amount of a compound according to thepresent invention, or a physiologically functional derivative, solvateor salt thereof to a subject in need thereof.

Furthermore, the present invention relates to the use of a compoundaccording to the present invention, or a physiologically functionalderivative, solvate or salt thereof in the treatment or prevention ofthe medical conditions specified herein.

16. A method of treatment or prevention of a medical condition selectedfrom the group comprising autoimmune inflammatory disorders, CNSdisorders, sleeping disorders, and proliferative diseases includingcancer, which comprises the administration of an effective amount of acompound according to the present invention, in particular according toany of the above items 1 to 12, or a physiologically functionalderivative, solvate or salt thereof to a subject in need thereof.

17. Use of a compound according to the present invention, in particularaccording to any of the above items 1 to 12, or a physiologicallyfunctional derivative thereof, solvate or salt in the manufacture of amedicament for the treatment or prevention of a medical conditionselected from the group comprising autoimmune inflammatory disorders,CNS disorders, sleeping disorders, and proliferative diseases includingcancer.

18. Process for the preparation of a compound according to the presentinvention, in particular according to any of the above items 1 to 12,wherein A is an —CONH— or —NHCO—, the process comprising the step ofcoupling a compound of below Formula IV with a compound of below formulaII;

wherein Y, L and X are as defined above, and

wherein either R¹ is NH₂ and R² is COOH or COOCl, or wherein R² is NH₂and R¹ is COOH or COOCl, particularly R¹ is NH₂ and R² is COOH or COOCl.

The compounds of the present invention interact with Casein kinase deltaand/or epsilon, suggesting their applicability in prevention and/ortherapy of medical conditions wherein the function of Casein kinasedelta and/or epsilon plays a role.

Particularly, the difluoromethylenedioxy group of the compoundsaccording to the present invention unexpectedly shows two molecularinteractions with the side chain residues of glutamyl 52 and tyrosin 56of Casein kinase delta. Such additional binding interaction in additionto the hydrogen binding network of the benzimidazol heterocycle of thecentral moiety was not known from the prior art, and contributes to thefavourable inhibitory activity of the compounds according to the presentinvention.

This unexpected finding shows, that an acyl amino-benzimidazolderivative containing a difloromethylendioxo residue on the benzole ringhas specific interactions to kasein kinase delta.

The following definitions are meant to further define certain terms usedin the context of the present invention. If a particular term usedherein is not specifically defined, the term shoud not be considered tobe indefinite. Rather, such terms are to be construed in accordance withtheir meaning as regularly understood by the skilled artisan in thefield of art to which the invention is directed, particularly in thefield of organic chemistry, pharmaceutical sciences and medicine.

As used herein, an alkyl group is to be understood to encompass alkanyl,alkenyl, alkynyl, wherein alkanyl means a completely saturatedhydrocarbon chain, alkenyl means a hydrocarbon chain comprising at leastone carbon-carbon double bond, alkynyl means a hydrocarbon chaincomprising at least one carbon-carbon triple bond (including ahydrocarbon chain comprising one or more carbon-carbon double bonds andat least one carbon-carbon triple bond). In the context of the presentinvention, an alkanyl group, if not stated otherwise, particularlydenotes a linear or branched C₁-C₆-alkanyl, particularly a linear orbranched C₁-C₅-alkanyl; an alkenyl group, if not stated otherwise,particularly denotes a linear or branched C₂-C₆-alkenyl; and an alkynylgroup, if not stated otherwise, particularly denotes a linear orbranched C₂-C₆-alkynyl group. In particular embodiments the alkyl groupis selected from the group comprising —CH₃, —C₂H₅, —CH═CH₂, —C≡CH,—C₃H₇, —CH(CH₃)₂, —CH₂—CH═CH₂, —C(CH₃)═CH₂, —CH═CH—CH₃, —C≡C—CH₃,—CH₂—C≡CH, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,—C₆H₁₃, —C(R′)₃, —C₂(R′)₅, —CH₂—C(R′)₃, —C₃(R′)₇, —C₂H₄—C(R′)₃,—C₂H₄—CH═CH₂, —CH═CH—C₂H₅, —CH═C(CH₃)₂, —CH₂—CH═CH—CH₃, —CH═CH—CH═CH₂,—C₂H₄—C≡CH, —C≡C—C₂H₅, —CH₂—C≡C—CH₃, —C≡C—CH═CH₂, —CH═CH—C≡CH,—C≡C—C≡CH, —C₂H₄—CH(CH₃)₂, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅,—CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —C₃H₆—CH═CH₂,—CH═CH—C₃H₇, —C₂H₄—CH═CH—CH₃, —CH₂—CH═CH—C₂H₅, —CH₂—CH═CH—CH═CH₂,—CH═CH—CH═CH—CH₃, —CH═CH—CH₂—CH═CH₂, —C(CH₃)═CH—CH═CH₂,—CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂, —CH₂—CH═C(CH₃)₂, C(CH₃)═C(CH₃)₂,—C₃H₆—C≡CH, —C≡C—C₃H₇, —C₂H₄—C≡C—CH₃, —CH₂—C≡C—C₂H₅, —CH₂—C≡C—CH₃,CH═CH₂, —CH₂—CH═CH—C≡CH, —CH₂—C≡C—C≡CH, —C≡C—CH═CH—CH₃, —CH═CH—C≡C—CH₃,—C≡C—C—CH₃, —C≡C—CH₂—CH═CH₂, —CH═CH—CH₂—C≡CH, —C≡C—CH₂—C≡CH,—C(CH₃)═CH—CH═CH₂, —CH═C(CH₃)—CH═CH₂, —CH═CH—C(CH₃)═CH₂,—C(CH₃)═CH—C≡CH, —CH═C(CH₃)—C≡CH, —C≡C—C(CH₃)═CH₂, —C₃H₆—CH(CH₃)₂,—C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,—CH(CH₃)—C(CH₃)₃, —C₄H₈—CH═CH₂, —CH═CH—C₄H₉, —C₃H₆—CH═CH—CH₃,—CH₂—CH═CH—C₃H₇, —C₂H₄—CH═CH—C₂H₅, —CH₂—C(CH₃)═C(CH₃)₂,—C₂H₄—CH═C(CH₃)₂, —C₄H₈—C≡CH, —C≡C—C₄H₉, —C₃H₆—C≡C—CH₃, —CH₂—C≡C—C₃H₇,and —C₂H₄—C≡C—C₂H₅. The alkyl, alkanyl, alkenyl, and alkynyl groups asdefined above, including the groups enumerated as examples andparticular embodiments thereof, are optionally substituted by one ormore sub stituents R′.

As used herein, an aryl group denotes an aromatic mono- or polycyclichydrocarbon ring system, which may optionally be fused to one or morecycloalkyl or heterocyclyl rings, and wherein the total number of ringatoms in the aryl group is six to fourteen, particularly six to ten. Thepoint of attachment of of said aryl group to the central moiety may belocated on the mono- or polycyclic hydrocarbon ring system or on theoptionally fused cycloalkyl or heterocyclyl ring. Examples of the arylgroup are phenyl, naphthyl, indenyl, azulenyl, fluorenyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydroindenyl,1,5-dihydro-s-indacenyl, 1,6-dihydro-as-indacenyl,1H-cyclopenta[a]naphthyl and 1H-cyclopenta[b]naphthyl, phenalenyl,phenanthrenyl, anthracenyl, 1,6-dihydropentalenyl,1,6a-dihydropentalenyl, 1,2,3,4-tetrahydroanthracenyl,1,2,3,4-tetrahydrophenanthrenyl,2,3-dihydro-1H-cyclopenta[a]naphthalenyl,2,3-dihydro-1H-cyclopenta[b]naphthalenyl, 2,3-dihydro-1H-phenalenyl,2,3-dihydrobenzo[b]thiophenyl-1,1-dioxide,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzo[b]thiophenyl,2,3-dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzoimidazolyl,benzo[d][1,3]dioxolyl, chromanyl, indazolinyl and indolinyl. Inparticular embodiments, the aryl group is phenyl,2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzofuranyl,2-oxo-2,3-dihydrobenzoimidazolyl or benzo[d][1,3]dioxolyl, moreparticularly phenyl. The aryl groups as defined above, including thegroups enumerated as examples and particular embodiments thereof, areoptionally substituted by one or more sub stituents R′.

As used herein, a heteroaryl group denotes an aromatic mono- orpolycyclic hydrocarbon ring system wherein one or more carbon atoms arereplaced by heteroatoms independently selected from the group comprisingO, N and S, wherein the aromatic mono- or polycyclic hydrocarbon ringsystem may optionally be fused to one or more cycloalkyl or heterocyclylrings, and wherein the total number of ring atoms in the heteroarylgroup is five to fourteen, particularly five to ten, more particularlyfive or six. The point of attachment of of said heteroaryl group to thecentral moiety may be located on the mono- or polycyclic hydrocarbonring system or on the optionally fused cycloalkyl or heterocyclyl ring.Examples of the heteroaryl group are thiadiazole, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isooxazol-3-yl,isooxazol-4-yl, isooxazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, benzooxazol-2-yl,benzooxazol-4-yl, benzooxazol-5-yl, benzoisooxazol-3-yl,benzoisooxazol-4-yl, benzoisooxazol-5-yl, 1,2,5-oxadiazol-4-yl,1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,3,4-thiadiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl,isothiazol-5-yl, benzoisothiazol-3-yl, benzoisothiazol-4-yl,benzoisothiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl,1,2,5-thiadiazol-4-yl, 4-imidazolyl, benzoimidazol-4-yl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyrid-5-yl, pyrid-6-yl, 3-pyridazinyl, 4-pyridazinyl,2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl,1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, phenazinyl,carbazolyl, phenoxazinyl, indolizine, 2-indolyl, 3-indolyl, 4-indolyl,5-indolyl, 6-indolyl, 7-indolyl, 1-isoindolyl, 3-isoindolyl,4-isoindolyl, 5-isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl,3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl,benzo[b]furanyl, benzofurazane, benzothiofurazane, benzotriazol-1-yl,benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl,benzotriazol-7-yl, benzotriazine, benzo[b]thiophenyl, benzimidazolyl,benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, or tetrahydroisoquinolinyl, purine,phthalazine, pteridine, thiatetraazaindene, thiatriazaindene,isothiazolopyrazine, 6-pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl,benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl,benz-imidazol-5-yl, benzimidazol-6-yl, benzimidazol-7-yl, tetrazole,tetrahydro-thieno[3,4-d]imidazol-2-one, pyrazolo[5,1-c][1,2,4]triazine,isothiazolopyrimidine, pyrazolotriazine, pyrazolopyrimidine,imidazopyridazine, imidazopyrimidine, imidazopyridine,imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine,triazolopyrimidine, or triazolopyridazine. The heteroaryl groups asdefined above, including the groups enumerated as examples andparticular embodiments thereof, are optionally substituted by one ormore substituents R′.

As used herein, a cycloalkyl group denotes a non-aromatic, mono- orpolycyclic completely saturated or partially unsaturated hydrocarbonring system. Said cycloalkyl is particularly mono- or bicyclic, moreparticularly monocyclic. Said cycloalkyl is particularly completelysaturated. Said cycloalkyl particularly comprises 3 to 10 carbon atoms,more particularly 5 to 7 carbon atoms. Even more particularly, saidcycloalkyl is selected from the group comprising cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-norbornyl,2-norbonryl, 7-norbornyl, 1-adamantyl, and 2-adamantyl, yet even moreparticularly said cycloalkyl is cyclohexyl or cyclopropyl. Thecycloalkyl groups as defined above, including the groups enumerated asexamples and particular embodiments thereof, are optionally substitutedby one or more substituents R′.

As used herein, a heterocyclyl group denotes a non-aromatic mono- orpolycyclic completely saturated or partially unsaturated hydrocarbonring system, wherein one or more of the carbon atoms are replaced by aheteroatom independently selected from N, O, or S. Said heterocyclyl isparticularly mono- or bicyclic, more particularly monocyclic. Saidheterocyclyl is particularly completely saturated. Said heterocyclylparticularly comprises a sum of 5 to 10 carbon and heteroatoms, moreparticularly a sum of 5 to 7 carbon and heteroatoms, even moreparticularly a sum of 6 carbon and heteroatoms. Even more particularlysaid heterocyclyl is selected from the group comprising morpholinyl,piperidinyl, dioxanyl, piperazinyl, thiomorpholinyl, piperidinyl,pyrrolidinyl, tetrahydrofuranyl, isoxazolidinyl, thiomorpholinyl,tetrahydrothiofuranyl and tetrahydropyranyl, more particularly selectedfrom the group comprising morpholinyl, piperidinyl, dioxanyl,piperazinyl, thiomorpholinyl, piperidinyl, and pyrrolidinyl. Theheterocyclyl groups as defined above, including the groups enumerated asexamples and particular embodiments thereof, are optionally substitutedby one or more sub stituents R′.

As used herein, a halo or halogen group denotes fluorine, chlorine,bromine or iodine; particularly chlorine or fluorine.

As used herein, a haloalkyl group denotes an alkyl group wherein one ormore, particularly at least half, more particularly all of the hydrogenatoms on the hydrocarbon chain are replaced by halogen atoms. Thehaloalkyl group is particularly selected from the group comprising—C(R¹⁰)₃, —CH₂—C(R¹⁰)₃, —C(R¹⁰)₂—CH₃, —C(R¹⁰)₂—C(R¹⁰)₃,—C(R¹⁰)₂—CH(R¹⁰)₂, —CH₂—CH(R¹⁰)₂, —CH(R¹⁰)—C(R¹⁰)₃, —CH(R¹⁰)—CH₃, and—C₂H₄—C(R¹⁰)₃, more particularly —C(R¹⁰)₃, wherein R¹⁰, R¹⁰ representshalogen, particularly F. More particularly, haloalkyl is —CF₃, —CHF₂,—CH₂CF₃, or CF₂Cl.

As used herein, an alkoxy group denotes an O-alkyl group, the alkylgroup as defined above. The alkoxy group is particularly selected fromthe group comprising methoxy, ethoxy and propoxy, more particularlymethoxy.

As used herein, alkylthio group denotes an —S-alkyl group, the alkylgroup as defined above, particularly methylthio.

As used herein, a haloalkoxy group denotes an O-haloalkyl group,haloalkyl group being defined as defined above. The haloalkoxy group isparticularly selected from the group comprising —OC(R¹⁰)³,—OCR¹⁰(R^(10′))₂, —OCH₂—C(R¹⁰)₃, and —OC₂H₄—C(R¹⁰)₃, wherein R¹⁰,R^(10′) represent F, Cl, Br or I, particularly F.

An alkylamino group is an NH-alkyl or N-dialkyl group, the alkyl groupas defined above, particularly mono- or dimethylamino, mono- ordiethylamino or isopropylamino, more particularly dimethylamino.

An arylalkyl or aralkyl group denotes a linear or branched C1-C6-alkylas defined herein substituted with at least one aryl group as definedherein. Exemplary arylalkyl groups include styryl, benzyl, phenylethyl,1-(naphthalen-2-yl)ethyl, particularly the arylalkyl group is styryl or1-(naphthalen-2-yl)ethyl, wherein styryl is particularly optionallysubstituted at its phenyl part as defined above for the aryl group. Inother particular embodiments, the arylalkyl group is benzyl, styryl or1-(naphthalen-2-yl)ethyl.

R′ is independently selected from the group comprising halogen,C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, aryl,heteroaryl, cycloalkyl, heterocyclyl, —S—C₁₋₆-alkyl, —S—C₁₋₆-haloalkyl,nitro, —NH₂, —N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl),—CONH₂, —CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl),—COOH, —SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), and —CN,particularly selected from the group comprising F, Cl, C₁₋₃-alkyl,C₁₋₃-haloalkyl, C₁₋₃-haloalkoxy, OH, C₁₋₃-alkoxy, phenyl, pyridyl,pyrrolyl, thiophenyl, furanyl, cyclopentyl, cyclohexyl, piperidinyl,piperazinyl, tetrahydrofuranyl, morpholinyl, —S—C₁₋₃-alkyl,—S—C₁₋₃-haloalkyl, nitro, —NH₂, —N(C₁₋₃-alkyl)₂, —NH(C₁₋₃-alkyl),—NHCO(C₁₋₃-alkyl), —CONH₂, —CONH(C₁₋₃-alkyl), —CO(C₁₋₃-alkyl), —COH,—COO(C₁₋₃-alkyl), —COOH, —SO₂NH₂, —SO₂NH(C₁₋₃-alkyl), —SO₂(C₁₋₃-alkyl),and —CN, more particularly selected from the group comprising F, Cl,methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, OH,methoxy, methylsulfanyl, trifluoromethylsulfanyl, nitro, —NH₂,dimethylamino, diethylamino, diisopropylamino, methylamino, ethylamino,isopropylamino, —NHCO-methyl, —CONH₂, —CONH-methyl, —CONH-ethyl,—CO-methyl, —CO-ethyl, —COO-methyl, —COO-ethyl, —COOH, —SO₂NH₂,—SO₂NH-methyl, —SO₂-methyl, —SO₂NH-ethyl, —SO₂-ethyl, and —CN, even moreparticularly selected from the group comprising F, Cl, methyl, ethyl,isopropyl, trifluoromethyl, trifluoromethoxy, OH, methoxy, nitro, —NH₂,dimethylamino, diethylamino, methylamino, ethylamino, —CONH₂,—COO-methyl, —COO-ethyl, —COOH, and —CN, yet even more particularlyselected from the group comprising F, Cl, methyl, trifluoromethyl,trifluoromethoxy, OH, methoxy, nitro, —NH₂, and —CN, most particularlyselected from the group comprising F, Cl, methyl, trifluoromethyl,trifluoromethoxy, OH, and methoxy. Particularly, R′ is not substitutedby further groups.

Where chemically feasible from the viewpoint of molecule stabilityand/or chemical valence rules, a nitrogen heteroatom as defined herein,e.g. in the context of “heteroaryl” and “heterocycle”, may include theN-oxide.

Where chemically feasible from the viewpoint of molecule stability underphysiological conditions and/or chemical valence rules, the definitionof a sulfur heteroatom as defined herein, e.g. in the context of“heteroaryl” and “heterocycle”, may include the sulfur oxide and/or thesulfur dioxide, respectively.

As used herein the term “substituted with” or “substituted by” meansthat one or more hydrogen atoms connected to a carbon atom or heteroatomof a chemical group or entity are exchanged with a substituent group,respectively; e.g. substituted aryl comprises 4-hydroxyphenyl, whereinthe H-atom in the 4-position of the phenyl group is exchanged with ahydroxyl group. Said hydrogen atom(s) to be replaced may be attached toa carbon atom or heteroatom, and may be expressedly shown in a specificformula, such as for example in an —NH— group, or may not expressedly beshown but intrinsically be present, such as for example in the typical“chain” notation which is commonly used to symbolize e.g. hydrocarbons.The skilled person will readily understand that particularly suchsubstituents or substituent patterns are excluded, which lead tocompounds which are not stable and/or not accessible via the synthesismethods known in the art.

As used herein, the term “central moiety” means theN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)part of the molecule which is shown in the below graphic representation.

Unless specified otherwise, references to the compounds according to thepresent invention include the pharmaceutically acceptable derivatives,solvates or salts thereof as described herein, as well as to salts ofsaid pharmaceutically acceptable derivatives, solvates of salts andpharmaceutically acceptable derivatives, and optionally solvates ofsalts of pharmaceutically acceptable derivatives.

As used herein, the term “pharmaceutically acceptable derivative” of acompound according to the present invention is for instance a prodrug ofsaid compound, wherein at least one of the following groups arederivatized as specified in the following: A carboxylic acid group isderivatized into an ester, a hydroxyl group is derivatized into anester, a carboxylic acid is derivatized into an amide, an amine isderivatized into an amide, a hydroxyl group is derivatized into aphosphate ester.

As used herein, the term “tautomer” used in reference to the compounsaccording to the present invention, in particular includes tautomersthat typically form with respect to substituted benzimidazol groups. Asan illustration two tautomeric forms of an exemplary substitutedbenzimidazol moiety, as is present in the compounds according to thepresent invention, are shown:

The compounds according to the present invention are to be understood tocomprise all tautomeric forms thereof, even if not expressedly shown inthe formulae described herein, including Formulae (I) and (Ia).Throughout this specification, whenever a chemical formula, generic orotherwise, discloses a compound having a 1H-benzimidazole moiety that isunsubstituted at the 1 position, as shown on the left-hand side of theabove exemplary illustration, said chemical formula it is to beunderstood to implicitly also relate to compounds wherein thebenzimidazole moiety is tautomerized to form the structure as shown onthe right-hand side of the above exemplary illustration.

The compounds of Formulae (I) and (Ia) as defined herein are to beunderstood to encompass, where applicable, all stereoismers of saidcompounds, unless specified otherwise. The term “stereoisomer” as usedherein refers to a compound with at least one stereogenic centre, whichmay be R- or S-configured, as defined by the according IUPAC rules, andencompasses enantiomers and diastereomers as commonly understood by theskilled person. It has to be understood, that in compounds with morethan one stereogenic centre, each of the individual stereogenic centresmay independently from each other be R- or S-configured. The term“stereoisomer” as used herein also refers to salts of the compoundsherein described with optically active acids or bases.

In the present invention, the salts of the compounds according to thepresent invention are particularly pharmaceutically acceptable salts ofthe compounds according to the present invention. Pharmaceuticallyacceptable salts are such salts which are usually considered by theskilled person to be suitable for medical applications, e.g. becausethey are not harmful to subjects which may be treated with said salts,or which give rise to side effects which are tolerable within therespective treatment. Usually, said pharmaceutically acceptable saltsare such salts which are considered as acceptable by the regulatoryauthorities, such as the US Food and Drug Administration (FDA), theEuropean Medicines Agency (EMA), or the Japanese Ministry of Health,Labor and Welfare Pharmaceuticals and Medical Devices Agency (PMDA).However, the present invention in principle also encompasses salts ofthe compounds according to the present invention which are as such notpharmaceutically acceptable, e.g. as intermediates in the production ofthe compounds according to the present invention or physiologicallyfunctional derivatives thereof, or as intermediates in the productionpharmacologically acceptable salts of the compounds according to thepresent invention or physiologically functional derivatives thereof.

In each case, the skilled person can readily determine whether a certaincompound according to the present invention or pharmaceuticallyacceptable derivative thereof can form a salt, i.e. whether saidcompound according to the present invention or pharmaceuticallyacceptable derivative thereof has a group which may carry a charge, suchas e.g. an amino group, a carboxylic acid group, etc.

Exemplary salts of the compounds of the present invention are acidaddition salts or salts with bases, particularly pharmacologicallytolerable inorganic and organic acids and bases customarily used inpharmacy, which are either water insoluble or, particularly,water-soluble acid addition salts. Salts with bases may—depending on thesubstituents of the compounds of the present invention—also be suitable.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are also encompassed by thepresent invention and, if desired, may be converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore solvates and in particular hydrates of the compounds ofthe present invention as well as solvates and in particular hydrates ofthe salts and/or physiologically functional derivatives of the compoundsof the present invention. More particularly the invention encompasseshydrates of the compounds, salts and/or physiologically functionalderivatives according to the present invention, comprising one, two orone half water molecule, with respect to their stoichiometry.

As used herein, the term “room temperature”, “rt” or “r.t.” relates to atemperature of about 25° C., unless specified otherwise.

As used herein, the term “stable” specifies a compound in which thechemical structure is not altered when the compound is stored at atemperature from about −80° C. to about +40° C., particularly from about−80° C. to +25° C. in the absence of light, moisture or other chemicallyreactive conditions for at least one week, particularly at least onemonth, more particularly at least six months, even more particularly, atleast one year, and/or a compound which under IUPAC standard conditionsand in the absence of light, moisture or other chemically reactiveconditions maintains its structural integrity long enough to be usefulfor therapeutic or prophylactic administration to a patient, i.e. atleast one week. Compounds which are not stable as described above areparticularly not encompassed by the present invention. In particular,such compounds which at IUPAC standard conditions spontaneouslydecompose within a period of less then one day are regarded as not beingstable compounds. The skilled person will readily recognize, based onhis general knowledge in his field of expertise, which compounds andwhich substitution patterns result in stable compounds.

As used herein, the term “treatment” includes complete or partialhealing of a disease, prevention of a disease, alleviation of a diseaseor stop of progression of a given disease.

As used herein, the term “medicament” includes the compounds of formula(I) as described herein, pharmacologically acceptable salts orphysiologically functional derivatives thereof, which are to beadministered to a subject in pure form, as well as compositionscomprising at least one compound according to the present invention, apharmacologically acceptable salt or physiologically functionalderivative thereof, which is suitable for administration to a subject.

The compounds according to the present invention and theirpharmacologically acceptable salts and physiologically functionalderivatives can be administered to animals, particularly to mammals, andin particular to humans as therapeutics per se, as mixtures with oneanother or particularly in the form of pharmaceutical preparations orcompositions which allow enteral (e.g. oral) or parenteraladministration and which comprise as active constituent atherapeutically effective amount of at least one compound according tothe present invention, or a salt or physiologically functionalderivative thereof, in addition to e.g. one or more components selectedfrom the group comprising customary adjuvants, pharmaceuticallyinnocuous excipients, carriers, buffers, diluents, and/or othercustomary pharmaceutical auxiliaries.

The pharmaceutical compositions, medical uses and methods of treatmentaccording to the present invention may comprise the more than onecompound according to the present invention.

Pharmaceutical compositions comprising a compound according to thepresent invention, or a pharmaceutically acceptable salt orphysiologically functional derivative may optionally comprise one ormore further therapeutically active substances which are not compoundsof formula (I) according to the present invention. As used herein, theterm “therapeutically active substance” specifies a substance which uponadministration can induce a medical effect in a subject. Said medicaleffect may include the medical effect described herein for the compoundsof formula (I) of the present invention, but may also, in the case oftherapeutically active substances which are to be co-administered withthe compounds according to the present invention, include othermedicalsubstances, such as for example but not exclusively irinotecan,oxaliplatin, capecitabine, 5-fluorouracil, cetuximab (Erbitux),panitumumab (Vectibix), bevacizumab (Avastin), vincristine, vinblastine,vinorelbine, vindesine, taxol, amsacrine, etoposide, etoposidephospahte, Teniposide, actinomycin, anthracyclines, doxorubicin,valrubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin,mitomycin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamideand other kinase inhibitors.

The term “pharmaceutically acceptable” is well known to the skilledperson and particularly means that the respective entity is not harmfulto the subject to which the entity or the composition comprising theentity is administered, that said entity is stable and that said entityis chemically compatible (i.e. non-reactive) with other ingredients ofthe respective pharmaceutical composition.

Medicaments and pharmaceutical compositions according to the presentinvention, comprising at least one compound according to the presentinvention or a pharmacologically acceptable salt or a physiologicallyfunctional derivative therof include those suitable for oral, rectal,bronchial, nasal, topical, buccal, sub-lingual, vaginal or parenteral(including transdermal, subcutaneous, intramuscular, intrapulmonary,intravascular, intracranial, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by controlled release (e.g. sustained release,pH-controlled release, delayed, release, repeat action release,prolonged release, extended release) systems. Suitable examples ofcontrolled release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsulesor colloidal drug carriers e.g. polymeric nanoparticles, or controlledrelease solid dosage forms, e.g. core tablets or multi-layer tablets.

The production of medicaments or pharmaceutical compositions comprisingthe compounds according to the present invention and their applicationcan be performed according to methods which are well-known to themedical practitioner.

Pharmaceutically acceptable carriers used in the preparation of apharmaceutical composition or medicament comprising a compound accordingto the present invention, a pharmacologically acceptable salt orphysiologically functional derivative thereof, can be either solid orliquid. Solid form pharmaceutical compositions comprising a compoundaccording to the present invention, a pharmacologically acceptable saltor physiologically functional derivative thereof, include powders,tablets, pills, capsules, sachets, suppositories, and dispersiblegranules. A solid carrier may comprise one or more components, which mayalso act as diluents, flavouring agents, solubilizers, lubricants,suspending agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. The tabletting mixture can be granulated, sieved and compressedor direct compressed. Suitable carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, sachets and lozengesare included. Tablets, powders, capsules, pills, sachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into conveniently sized moulds,allowed to cool, and thereby to solidify. Compositions suitable forvaginal administration may be presented as peccaries, tampons, creams,gels, pastes, foams or sprays containing in addition to the activeingredient such carriers as are known in the art to be appropriate.Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The compounds according to the present invention may be formulated forparenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulation agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for re-constitutionwith a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral administration can be prepared bydissolving the active component in water and adding for example suitablecolorants, flavours, stabilizing and thickening agents, as desired.Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before administration, to liquid form preparationsfor oral administration. Such liquid forms include solutions,suspensions, and emulsions. These preparations may contain, in additionto the active component, for example colorants, flavours, stabilizers,buffers, artificial and natural sweeteners, dispersants, thickeners,solubilizing agents, and the like.

In an embodiment of the present invention the medicament is appliedtopically, e.g. in the form of transdermal therapeutic systems (e.g.patches) or topical formulations (e.g. liposomes, crèmes, ointment,lotion, gels, dispersion, suspension, spray, solution, foam, powder).This may be suitable to reduce possible side effects and, whereappropriate, limit the necessary treatment to those areas affected.

Particularly the medicament may comprise carrier materials orexcipients, including but not limited to a lipophilic phase (as forexample Vaseline, paraffines, triglycerides, waxes, polyalcylsiloxanes),oils (olive oil, peanut oil, castor oil, triglyceride oil), emulsifier(as for example lecithin, phosphatidylglyceroles, alkyl alcohols, sodiumlauryl sulfate, polysorbats, Cholesterol, sorbitan fatty acid ester,polyoxyethylene fatty acid glycerol and -ester, poloxamers),preservatives (for instance benzalkonium chloride, chlorobutanol,parabene or thiomersal), flavouring agents, buffer substances (forexample salts of acetic acid, citric acid, boric acid, phosphoric acid,tatric acid, trometamole or trolamine), solvents (for instancepolyethylenglycols, glycerol, ethanol, isopropanol or propyleneglycol)or solubilizers, agents for achieving a depot effect, salts formodifying the osmotic pressure, carrier materials for patches (forinstance polypropylene, ethylene-vinylacetat-copolymer, polyacrylates,silicon) or antioxidants (for example ascorbate, tocopherol,butylhydroxyanisole, gallic acid esters or butylhydroxytoluol).

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcolouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatine and glycerine or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Solutions or suspensions may be applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant such as a chlorofluorocarbon(CFC), for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the medicament may be provided in the form of a drypowder, for example a powder mix of the compound in a suitable powderbase such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form, for example incapsules or cartridges of, e.g., gelatine, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions for administration to the respiratory tract, includingintranasal compositions, the compound will generally have a smallparticle size for example of the order of 5 microns or less. Such aparticle size may be obtained by means known in the art, for example bymicronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are particularly in unit dosage forms.In such form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, sachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form. Tablets or capsules for oral administration andliquids for intravenous administration and continuous infusion areparticular compositions.

Further details on techniques for formulation and administration may befound in the 21^(st) edition of Remington's Pharmaceutical Sciences(Maack Publishing Co. Easton, Pa.).

The compounds of the present invention may be used in combination withradiation therapy, or in combination with radiation therapy and otheractive compounds, already known for the treatment of the medicalconditions disclosed herein, whereby a favourable additive or amplifyingeffect is noticed.

To prepare the pharmaceutical preparations, pharmaceutically inertinorganic or organic excipients can be used. To prepare pills, tablets,coated tablets and hard gelatine capsules, for example, lactose,cornstarch or derivatives thereof, talc, stearic acid or its salts, etc.can be used. Excipients for soft gelatine capsules and suppositoriesare, for example, fats, waxes, semi-solid and liquid polyols, natural orhardened oils etc. Suitable excipients for the production of solutionsand syrups are, for example, water, sucrose, invert sugar, glucose,polyols etc. Suitable excipients for the production of injectionsolutions are, for example, water, alcohols, glycerol, polyols orvegetable oils.

The dose can vary within wide limits and is to be suited to theindividual conditions in each individual case. For the above uses theappropriate dosage will vary depending on the mode of administration,the particular condition to be treated and the effect desired. Ingeneral, however, satisfactory results are achieved at dosage rates ofabout 1 to 100 mg/kg animal body weight particularly 1 to 50 mg/kg.Suitable dosage rates for larger mammals, for example humans, are of theorder of from about 10 mg to 3 g/day, conveniently administered once, individed doses 2 to 4 times a day, or in sustained release form.

The compounds of the present invention are suitable for the treatment ofinflammatory diorders and hyperproliferative diseases, such as benignand malignant forms of neoplasia, including cancer.

Exemplary types of cancer in the comtext of the present invention arehepatocarcinoma, adrenocortical carcinoma, AIDS-related cancersincluding AIDS-related lymphoma, anal cancer, basal cell carcinoma, bileduct cancer, bone cancer, brain tumors including brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma, malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermaltumors, visual pathway and hypothalamic glioma, breast cancer, bronchialadenomas/carcinoids, Burkitt's lymphoma, gastrointestinal, carcinoma ofunknown primary site, central nervous system lymphoma, cervical cancer,chronic myeloproliferative disorders, colon cancer, colorectal cancer,cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophagealcancer, extracranial germ cell tumor, extragonadal germ cell tumor,ovarian germ cell tumor, eye cancer including intraocular melanoma andretinoblastoma, gallbladder cancer, gastrointestinal carcinoid tumor,gestational trophoblastic tumor, glioma, childhood brain stem glioma,head and neck cancer, hematologic cancer, adult and childhood (primary)hepatocellular cancer, hypopharyngeal cancer, islet cell or pancreaticcancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia,adult and childhood acute myeloid leukemia, chronic lymphocyticleukemia, chronic myelogenous leukemia, hairy cell leukemia, lip andoral cavity cancer, liver cancer, lung cancer, including non-small celllung cancer and small cell lung cancer, Hodgkin's lymphoma,non-Hodgkin's lymphoma, primary central nervous system lymphoma,Waldenstrom's macroglobulinemia, merkel cell carcinoma, mesothelioma,metastatic squamous neck cancer with occult primary site, multipleendocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm,mycosis fungoides, myelodysplastic syndromes, myelodysplasticmyeloproliferative diseases, multiple myeloma, chronicmyeloproliferative disorders, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer,osteosarcoma/malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian low malignant potential tumor,pancreatic cancer, parathyroid cancer, penile cancer, pheochromocytoma,pineoblastoma and supratentorial primitive neuroectodermal tumors,pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonaryblastoma, prostate cancer, rectal cancer, renal pelvis and uretercancer, transitional cell cancer, rhabdomyosarcoma, salivary glandcancer, Ewing's sarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterinesarcoma, sezary syndrome, skin cancer, including melanoma andnon-melanoma skin cancer, small intestine cancer, squamous cellcarcinoma, gastric cancer, supratentorial primitive neuroectodermaltumors, testicular cancer, thymoma, thymoma and thymic carcinoma,thyroid cancer, trophoblastic tumor, gestational, endometrial uterinecancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom'smacroglobulinemia, Wilms' tumor.

In a more particular embodiment of the present invention, the compoundsof the present invention may be used in the treatment of the followingcancer types: Prostate, bladder, kidney (i.e. renal), muscle, ovary,skin, lung, pancreas, breast, cervix, colon, liver, connective tissue,placenta, bone, brain, uterus, salivary gland, or testes.

In particular embodiments of the present invention, in said cancer, thehedgehog signaling pathway is activated.

In particular embodiments of the present invention, in cells of saidcancer, the hedgehog signaling pathway is activated.

In the present invention patients wherein in said cancer, or in cells ofsaid cancer, the hedgehog signaling pathway is activated are in shortreferred to as “Hedgehog dependent patients”, and patients wherein insaid cancer, or in the cells of said cancer, the hedgehog signalingpathway is not activated are in short referred to as “Hedgehogindependent patients”. In the present invention, patients e.g. can beclassified as Hedgehog dependent patients if the cancer said patient issuffering from is described in the known scientific literature as beingassociated with aberrant Hedgehog signaling pathway activity. In thepresent invention, patients can also be stratified into Wnt dependentpatients and Wnt independent patients by a procedure comprising thesteps of

-   1) providing a sample from said patient, wherein said sample    comprises cancer cells from said patient,-   2) optionally subjecting said sample to a work-up step,-   3) adding a labeled antibody which specifically binds to at least    one protein playing a role in the hedgehog signaling pathway, or    -   adding a first antibody which specifically binds to at least one        protein playing a role in the hedgehog signaling pathway, and        subsequently adding a second antibody which specifically binds        to said first antibody, and wherein said second antibody is a        labeled antibody,-   4) washing said sample after step 3,-   5) determining whether said labeled antibody is detectable in said    sample after step 4),-   6) if in step 5) said marker moiety is detectable, classifying said    patient as Hedgehog dependent patient, and if in step 5) said marker    moiety is not detectable, classifying said patient as Hedgehog    independent patient.

Antibodies used in the present invention are typically monoclonalantibodies.

The label in said labeled antibody can be selected from any labeltypically used as antibody label in the field of biochemistry, cellularbiology, immunochemistry, etc., for a label selected from the groupcomprising a fluorescence label, a dye, a FRET label, a radioactivelabel. moiety, or an enzymatically active moiety. Said enzymaticallyactive moiety can process a reaction which in turn results in therelease of a detectable substance, e.g. a dye.

In the above method of stratifying patients into Hedgehog dependentpatients and Hedgehog independent patients, the work-up step is e.g. inparticular embodiments selected from the group comprising preservation,embedding, slicing and staining. Preservation can be performed bycryopreservation or fixation by e.g. formaldehyde or ethanol. Embeddingthe tumor material prepares it for slicing. Staining can be performedwith direct or indirect methods. For further information and examplessee DOI: 10.1354/vp.42-4-405 J. A. Ramos-Vara, Technical Aspects ofImmunohistochemistry, (2005) 42: 405 Vet Pathol.

In the context of the present invention, the expression “said labeledantibody is detectable” means that by the state of the art measurementmethods used for detecting said label, no signal relating to said labelis detectable, and/or said signal is not significant in relation to thebackground noise generated by said measurement method.

In the above method to stratify patients into Hedgehog dependentpatients and Hedgehog independent patients, washing step 4 is to removeunbound and/or unspecifically bound antibodies from step 3. Inparticular embodiments, said washing step comprises washing with abuffer, e.g. a PBS buffer, and optionally a serum protein, e.g. BSA.Washing step 4 can be repeated as necessary to obtain a suitablesignal/noise ratio, e.g. 2 or more, 3 or more, 4 or more times.

In certain embodiments of the above method to stratify patients intoHedgehog dependent cancer patients and Hedgehog independent cancerpatients, background signal by unspecific binding of antibodies isexcluded by an isotype control. This control can be utilized whenworking with monoclonal primary antibodies. A comparative sample treatedas above is incubated with antibody diluent, supplemented with anon-immune immunoglobulin of the same isotype (for example, IgG₁,IgG2_(A), IgG2_(B), IgM) and concentration as the aforementionedantibody. The sample is then incubated with the labeled antibody anddetection reagents. These steps will help ensure that what appears to bespecific staining was not caused by non-specific interactions ofimmunoglobulin molecules with the sample. Examples and a furtherdescription of this method can be found in “Tissue Microarrays—Methodsin Molecular Biology Volume 664, 2010, pp 113-126 , ImmunohistochemicalAnalysis of Tissue Microarrays; Ronald Simon, Martina Mirlacher, andGuido Sauter”.

In the context of the present invention the G protein-coupled receptorSmoothened is interchangeably abbreviated as “Smoothened” and “Smo”.

In the context of the present invention the expression “the activationof the hedgehog signaling pathway” in particular refers to theactivation of expression of primary target genes of the Hedgehogsignaling pathway, including GLI, HHIP, Ptch, more particularly of GLIexpression via the hedgehog pathway. Typically, GLI expression istriggered via binding of hedgehog to the Smo/Ptch (Smoothened/Patched)complex and thereupon GLI expression via signalling by Smo.

In the context of the present invention said at least one proteinplaying a role in the hedgehog signaling pathway can e.g. be selectedfrom the group comprising Patched, GLI, Smoothened, HHIP, Hedgehog andSUFU.

In the context of the present invention, the term “GLI” refers tomembers of the GLI protein family, such as GLI1, GLI2, GLI3 inparticular embodiments and, unless specified otherwise particularly toGLI1.

In general, and unless specified otherwise, the proteins, genes and/orgene expression products as defined herein in certain embodiments alsoinclude variants of said proteins, genes and gene expression products,such as isoforms, homologs and mutants thereof, which share at least 95%sequence homology, more particularly at least 97% sequence homology,even more particularly at least 99% sequence homology with , theproteins, genes and/or gene expression products as defined herein, andin the case of proteins and/or gene expression products in certainembodiments have essentially the same enzymatic activity as , theproteins and/or gene expression products as defined herein, whereinhowever the enzymatic activity of said variants may differ (i.e. behigher or lower than) from the proteins, and/or gene expression productsas defined herein by up to two orders of magnitude, particularly up toone order of magnitude, more particularly up to a factor of 2.

As used herein, the term “hedgehog signaling pathway” means a cellularsignaling pathway comprising an interaction with a protein of the familyknown as hedgehog proteins, such as e.g. the proteins commonly known as“sonic hedgehog” (UniProtKB/Swiss-Prot: Q15465), “indian hedgehog”(UniProtKB/Swiss-Prot: Q14623) and “desert hedgehog”(UniProtKB/Swiss-Prot: 043323) (Ingham and McMahon, 2001).

As used herein, the term “sample” in principle comprises samples fromnatural sources, such as a sample obtainable from a mammal, andartificial samples, which are obtainable by admixing severalingredients, wherein said ingredients may or may not be derived fromnatural sources, and may e.g. comprise ingredients selected from thegroup comprising synthetic and/or natural proteins, peptides, oligo- orpolynucleic acids, etc. In certain embodiments, samples are from naturalsources, which include bodily fluids and/or tissue samples, such asbodily fluid and/or a tissue sample obtainable from mammals. Saidsamples from natural sources can be used in the present invention withor without further processing after being obtained from their source,e.g. a mammal. Such processing can for instance comprise separation,fractionation, dilution, dispersion, mechanical treatment such assonification, or grinding, concentration, removal of certain componentsof said sample, or addition of compounds, such as salts, buffers,detergents, etc.

As used herein, the term “bodily fluid” or “body fluid” specifies afluid or part of a fluid originating from the body of a patient,including fluids that are excreted or secreted from the body of thepatient, including but not limited to blood, including peripheral blood,serum, plasma, urine, interstitial fluid, liquor, aqueous humour andvitreous humour, bile, breast milk, cerebrospinal fluid, endolymph,perilymph, ejaculate, gastric juice, mucus, peritoneal fluid, pleuralfluid, saliva, sweat, tears and vaginal secretion, particularlyperipheral blood, serum, plasma and urine. Said bodily fluid itself mayor may not comprise diseased and/or non-diseased cells.

As used herein, the term “tissue sample” specifies a non-fluid materialor solid originating from the body of a patient. Tissue samples include,but are not limited to samples of bone material, bone marrow, skin, hairfollicle, mucosa, brain, cartilage, muscles, lung, kidney, stomach,intestines, bladder and liver. Said tissue sample itself may or may notcomprise diseased cells, and may for instance be a sample taken from adiseased region of a patient's body, such as a biopsy of a tumor. Incertain embodiments the tissue sample is selected from skin, hairfollicle or oral mucosa.

In the embodiments of the present invention, the sample is obtained fromthe patient by any method and/or means commonly known to the skilledperson in the field of medicine, e.g. in certain embodiments bloodsample taking by venipuncture.

As used herein, the term “peripheral blood” specifies blood obtainedfrom the circulation remote from the heart, i.e. the blood in thesystemic circulation, as for example blood from acral areas.

As used herein, the term “whole blood” specifies unmodified bloodcomprising cells and fluid, as obtained from the donor of said blood,such as a patient.

As used herein, the term “small molecule” is to be understood ascommonly used in the field of pharmacology and means a low molecularweight organic compound which is not a polymer, and which usually has amolecular weight of about 800 Daltons or lower, particularly, 700Daltons or lower, more particularly 600 Daltons or lower, even moreparticularly 500 Daltons or lower. From a functional point of view, asmall molecule has to molecular weight which allows the molecule torapidly diffuse across cell membranes and/or reach the interior of amammalian cell.

In particular embodiments of the present invention, in said cancer, theWnt signaling pathway is activated.

In particular embodiments of the present invention, in cells of saidcancer, the Wnt signaling pathway is activated.

Multiple cancer types are associated with aberrant Wnt signaling pathwayactivity. As reviewed by Anastas and Moon (Nature Reviews Cancer, 2013,January, p. 11-26) hematological and solid tumors including AML, ALL,Breast cancer , Adrenocortical cancer, Colorectal Cancer, Oesophagealcarcinoma, Gastric Cancer, Glioblastoma, Lung Cancer, Prostate Cancer,Melanoma, HCC, Sarcoma, Ovarian carcinoma, Pancreatic Cancer exhibit anaberrant Wnt signaling pathway.

In the present invention patients wherein in said cancer, or in cells ofsaid cancer, the Wnt signaling pathway is activated are in shortreferred to as “Wnt dependent patients”, and patients wherein in saidcancer, or in the cells of said cancer, the Wnt signaling pathway is notactivated are in short referred to as “Wnt independent patients”. In thepresent invention, patients e.g. can be classified as Wnt dependentpatients if the cancer said patient is suffering from is described inthe known scientific literature as being associated with aberrant Wntsignaling pathway activity, such as e.g. the cancer types describedabove by Anastas and Moon. In the present invention, patients can alsobe stratified into Wnt dependent patients and Wnt independent patientsby by a procedure comprising the steps of

-   1) providing a sample from said patient, wherein said sample    comprises cancer cells from said patient,-   2) optionally subjecting said sample to a work-up step,-   3) adding a labeled antibody which specifically binds to at least    one protein playing a role in the Wnt signaling pathway, or    -   adding a first antibody which specifically binds to at least one        protein playing a role in the Wnt signaling pathway, and        subsequently adding a second antibody which specifically binds        to said first antibody, and wherein said second antibody is a        labeled antibody,-   4) washing said sample after step 3,-   5) determining whether said labeled antibody is detectable in said    sample after step 4),-   6) if in step 5) said marker moiety is detectable, classifying said    patient as Wnt dependent patient, and if in step 5) said marker    moiety is not detectable, classifying said patient as Wnt    independent patient.

Said patients can further be stratified into Wnt dependent patients andWnt independent patients by determining by providing a sample comprisingcancer cells of said patient, culturing said cancer cells in growthmedium and comparing whether growth of said cancer cells can beinhibited by a known Wnt inhibitor, as compared to a control group ofsaid cancer cells which is not treated said Wnt inhibitor.

The label in said labeled antibody can be selected from any labeltypically used as antibody label in the field of biochemistry, cellularbiology, immunochemistry, etc., for a label selected from the groupcomprising a fluorescence label, a dye, a FRET label, a radioactivelabel. moiety, or an enzymatically active moiety. Said enzymaticallyactive moiety can process a reaction which in turn results in therelease of a detectable substance, e.g. a dye.

In the above method of stratifying patients into Wnt dependent patientsand Wnt independent patients, the work-up step is e.g. in particularembodiments selected from the group comprising preservation, embedding,slicing and staining. Preservation can be performed by cryopreservationor fixation by e.g. formaldehyde or ethanol. Embedding the tumormaterial prepares it for slicing. Staining can be performed with director indirect methods. For further information and examples see DOI:10.1354/vp.42-4-405 J. A. Ramos-Vara, Technical Aspects ofImmunohistochemistry, (2005) 42: 405 Vet Pathol.

In the above method to stratify patients into Wnt dependent patients andWnt independent patients, washing step 4 is to remove unbound and/orunspecifically bound antibodies from step 3. In particular embodiments,said washing step comprises washing with a buffer, e.g. a PBS buffer,and optionally a serum protein, e.g. BSA. Washing step 4 can be repeatedas necessary to obtain a suitable signal/noise ratio, e.g. 2 or more, 3or more, 4 or more times.

In certain embodiments of the above method to stratify patients into Wntdependent cancer patients and Wnt independent cancer patients,background signal by unspecific binding of antibodies is excluded by anisotype control. This control can be utilized when working withmonoclonal primary antibodies. A comparative sample treated as above isincubated with antibody diluent, supplemented with a non-immuneimmunoglobulin of the same isotype (for example, IgG₁, IgG2_(A),IgG2_(B), IgM) and concentration as the aforementioned antibody. Thesample is then incubated with the labeled antibody and detectionreagents. These steps will help ensure that what appears to be specificstaining was not caused by non-specific interactions of immunoglobulinmolecules with the sample. Examples and a further description of thismethod can be found in “Tissue Microarrays—Methods in Molecular BiologyVolume 664, 2010, pp 113-126, Immunohistochemical Analysis of TissueMicroarrays; Ronald Simon, Martina Mirlacher, and Guido Sauter”.

In the context of the present invention the expression “the activationof the Wnt signaling pathway” in particular refers to the activation ofexpression of primary target genes of the Wnt signaling pathway, e.g.selected from the group comprising c-myc, Cyclin D, TCF1, LEF1,PPARdelta, c-jun, fra-1, MMP7, Axin2, ITF-2, CD44, BMP4, Survivin, VEGF,FGF18, FGF9, FGF20, Jagged, DKK1, LGR5, SOX2, SOX9, and OCT4.

In the context of the present invention said at least one proteinplaying a role in the Wnt signaling pathway can e.g. be selected fromthe group comprising Frizzled receptors (particularly FZD4, 5, 6, 7,ROR1, ROR2), Wnt ligands (particularly WNT1, 2, 3A, 5A, 7A), Wntinhibitory factors (particularly WIF1), secreted frizzled-relatedproteins (particularly SFRP3, 4), nuclear B-Catenin, and TCF/LEF familymembers (particularly LEF1, TCF7L2).

As used herein, the term “Wnt signaling pathway” means a cellularsignaling pathway comprising an interaction with a protein of the familyknown as Wnt proteins (UniProtKB/Swiss-Prot: e.g. P56704, O00755,Q9GZT5, O00744, Q93098, P41221, Q93097, O14905, O14904, Q9UBV4, O96014,Q9H1J7, P56706, Q9Y6F9, Q9H1J5, P56705, P56703, P09544, or P04628).

General Synthesis Procedure

In the following description of the synthesis procedures for compoundsof the present invention, which are exemplified for the amides ofFormula (Ia), the residues X, L and Y, where present, have the meaningas defined above.

EXAMPLES 1. Synthesis of Precursors 1.1 Synthesis ofN-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide

A solution of 5-Amino-2,2-difluoro-1,3-benzodioxole (26.0 g, 150.186mmol) in dry toluene (410 ml) and acetic anhydride (16.2 ml, 1.15 eq.)was stirred at 100° C. for 2 h.

Subsequently, the solvent was removed under reduced pressure. The crudeproduct was dissolved in 100 ml methanol to remove traces of aceticanhydride. The solvent was subsequently evaporated. The obtained crudeproduct was recrystallized from toluene. The obtained product wasfiltered off and dried under high vacuo to obtain greyish-beige crystals(30.5 g, 92.5% yield, 98% purity).

¹H NMR (DMSO-d₆+CCl₄): 2.04 (3H, s, CH₃), 7.20-7.23 (1H, dd, CH-arom.),7.30-7.33 (1H, s, CH-arom.), 7.74-7.75 (1H, d, CH-arom.), 10.12 (1H, s,NH).

1.2 Synthesis ofN-(2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)acetamide

N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetamide (11.39 g, 52.938 mmol)was dissolved in glacial acetic acid (50.4 ml). To the resulting mixturewas added dropwise a mixture of fuming nitric acid (6.1 ml, 3.35 eq.) inglacial acetic acid (20.2 ml, 0.28 eq.). After addition, the reactionmixture was stirred for 22 h at room temperature. The reaction mixturewas stirred at 60° C. overnight.

Subsequently, the reaction mixture was poured into a of ice and watermixture. The resulting precipitate was filtered off by suctionfiltration. The crude product was then purified by column chromatographyon a silica gel flash column (eluent DCM:MeOH 95:5). The product wasisolated and concentrated in vacuo to obtain a yellow solid (6.7 g, 49%yield, 100% purity).

¹H NMR (DMSO-d₆+CCl₄): 2.09 (3H, s, CH₃), 7.76 (1H, s, CH-arom.), 8.15(1H, s, CH-arom.), 10.33 (1H, s, NH).

1.3 Synthesis of 2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-amine

N-(2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-yl)acetamide (6.76 g,25.985 mmol) was dissolved in methanol (676 ml). The reaction mixturewas cooled to 0° C. Then sodium methylate (ca. 25% in methanol) (30.3ml, 5 eq.) was added and the resulting mixture was stirred for 20 min at0° C. and subsequently for 25 min at 5° C. The reaction was theninterrupted by adding glacial acetic acid (37.2 ml, 25 eq.).

The solvent was removed under reduced pressure, whereupon a liquid-oilyresidue formed. The last traces of solvent, together with the remainingglacial acetic acid, were removed by a two-fold co-evaporation withtoluene. Upon addition of toluene, a white solid precipitated, which wasfiltered off by suction filtration. The filtrate was concentrated invacuo and dried under reduced pressure. The crude product was purifiedby column chromatography on a silica gel flash column (eluent DCM:MeOH95:5). The first spot as observed by thin layer chromatography under thesame eluent conditions was isolated and the fractions containing theproduct were collected, concentrated in vacuo and dried to obtain anorange powder.

¹H NMR (DMSO-d6; CCl₄): 6.95 (1H, s, CH-arom.), 7.79 (2H, s, NH₂), 7.95(1H, s, CH-arom.).

1.4 Synthesis of 2,2-difluorobenzo[d][1,3]dioxole-5,6-diamine

2,2-difluoro-6-nitrobenzo[d][1,3]dioxol-5-amine (770 mg, 3.53 mmol) wasdissolved in dry methanol (100 ml) under an argon atmosphere andhydrogenated using Raney Nickel as catalyst for 1 h at room temperature.

The reaction mixture was filtered over CELLITE® and washed withmethanol. The solvent was evaporated and concentrated in vacuo. A purplesolid precipitated and was dried under reduced pressure. The crudegreyish product (530 mg, 53% yield) was purified by columnchromatography on a silica gel flash column (eluent DCM:MeOH 95:5). Theselected fractions were combined and concentrated in vacuo. The crudeproduct was precipitated as a hydrochloride using a 1.25 M hydrogenchloride solution in ethanol and an excess of ethyl acetate. Theresulting suspension was stirred overnight. Subsequently, the solid wasfiltered off Afterwards the obtained2,2-difluorobenzo[d][1,3]dioxole-5,6-diamine hydrochloride was dissolvedin water and extracted with ethylacetate. The aqueous layer wasalkalized to pH 8-10 and extracted with ethyl acetate. The organic layerwas then dried over magnesium sulfate, concentrated in vacuo and driedto obtain a brown solid (98% purity).

¹H NMR (DMSO-d6+CCl₄): 4.52 (4H, s, 2×NH₂), 6.52 (2H, s, CH-arom.).

1.5 Synthesis of2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-aminehydrobromide

To a solution of 5,6-Diamino-2,2-difluoro-1,3-benzodioxole (4.91 g,0.0261 mol) in dry methanol (98 ml) was added cyanogen bromide (3.23 g,1.3 eq.). The reaction mixture was stirred overnight at roomtemperature.

The reaction mixture was subsequently concentrated in vacuo. The residuewas then washed with dichloromethane and the precipitate was filteredoff and dried to obtain a brown solid (6.72 g, 88% yield, 98% purity).

¹H NMR (DMSO-d6+CCl₄): 7.47 (2H, s, 2×CH-arom.), 8.46 (2H, s, NH₂),12.58 (1H, s, NH).

2. Synthesis of Final Compounds (I)

2.1 General Procedure 1

To a solution of II (1-2 eq.) in dry DMF, dioxane or dichloromethane,particularly dry DMF (dimethylformamide) (3-10 ml) were added IV (1mmol). HBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluroniumhexafluorophosphate) (1-1.4 eq.), DIPEA (N,N-Diisopropylethylamine) (1-5eq.) or triethylamine (5 eq.), particularly DIPEA, and optionally DMAP(4-Dimethylaminopyridine) (0.1 eq.) were also added to the reactionmixture. The reaction temperature was usually in the range of from rt to85° C., particularly rt. The reaction was usually allowed to processovernight (which as used herein specifies a duration of approximatelybetween 12 and 24 h, depending on the reaction velocity).

After completion of the reactions, the reaction solution was subjectedto one or more after-treatments including:

A) Extraction with organic solvents: The residue obtained from thereaction was dissolved in an organic solvent (such as ethyl acetate ordichloromethane) and was washed at least once with an aqueous 5% NaHCO₃,aqueous 5% citric acid and water. The organic layer was dried overmagnesium sulfate and concentrated in vacuo.

B) Chromatography: The crude product obtained from the reaction waspurified by column chromatography on a silica gel flash column, bypreparative TLC (thin layer chromatography) or preparative HPLC (highpressure liquid chromatography) with a defined eluent proportion. Aftercompletion of the reaction, the crude product was purified by siliga gelflash column chromatography (CHCl₃/EtOH=80:1+1 drop of HOAc).

C) Recrystallization: The crude product was crystallized from ethanol(with activated carbon).

D) Precipitation: After completion of the reaction, the reaction mixturewas diluted with water, hexane or an aqueous Na₂CO₃-solution and/or waspoured into ice water and the formed precipitate was filtered off.

E) Washing: The obtained solid (e.g. obtained by filtration) was washedwith water, aqueous HCl or Na₂CO₃-solution and/or organic solvents.

F) Suspending, followed by filtration: The crude product was suspendedin Et₂O (diethyether), filtered off and dried.

G) Neutralization and recovery: After completion of the reaction, thesolvent was evaporated in vacuo, water was added and the precipitate wasformed. An aqueous 3% ammonia solution, or alternatively a sodiumhydrogen carbonate solution was added to the suspension till pH=8. After30 min of stirring the precipitate was filtered off or the dissolvedproduct was extracted.

2.2 Synthesis ofN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxamide(1)

2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-amine(3.28 mmol) and 2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxylicacid (3.28 mmol) were dissolved in dry dimethylformamide,2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate(HBTU) (3.28 mmol) and N,N-Diisopropylethylamine (DIPEA) (6.55 mmol)were added and the reaction mixture was stirred for 16 h at 85° C. Thereaction mixture was then concentrated in vacuo. The residue wasdissolved in EtOAc and was washed twice with an aqueous 5% sodiumhydrogen carbonate solution, aqueous 5% citric acid solution and water.The organic layer was dried over magnesium sulfate and was concentratedin vacuo. The product was purified by silica gel flash chromatographywith petrol ether/ethyl acetate. ¹H NMR (DMSO+d₆; CCl₄): 7.48 (2H, s,CH-arom.), 7.54-7.59 (2H, m, CH-arom.), 7.70-7.76 (1H, m, CH-arom.),7.80-7.83 (1H, dd, CH-arom.), 8.35 (1H, s, CH-thiazol), 11.14 (1H, s,NH), 12.49 (1H, s, NH), 13.12 (1H, s, NH).

2.3 General Procedure 2

II (1-1.5 eq.) was added to the suspension of IV (1 eq.) in dry pyridine(1-3 ml). The resulting mixture was stirred at rt overnight.

After completion of the reaction, the reaction solution, wherenecessary, was subjected to after-treatments such as the ones definedabove.

2.4 Synthesis ofN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide(49)

Benzoylchloride (0.179 g, 1.5 eq.) was added to the suspension of IV(0.25 g, 0.85 mmol) in dry pyridine (3 ml). The resulting mixture wasstirred at rt overnight. The reaction mixture was diluted with water (20ml) and the formed precipitate was filtered off, washed with water andrecrystallized from ethanol to obtain a pure product (0.1 g, 37% yield).¹H NMR (400 MHz, DMSO-d₆+CCl₄): 7.32 (2H, s, CH-arom.), 7.44-7.54 (2H,m, CH-arom.), 7.54-7.64 (1H, m, CH-arom.), 8.13 (2H, d, CH-arom.), 12.29(2H, s, NH).

2.5 General Procedure 3

I (1-1.5 eq.) was refluxed in SOCl₂ (3-5 ml) for 2 h. An excess of SOCl₂was evaporated in vacuo and pyridine (3 ml) was added to the resultingresidue. The mixture was then stirred for 10 min., IV (1 mmol) was addedand the resulting mixture was stirred overnight at rt. After completionof the reaction, the reaction solution was subjected, where necessary,to after-treatments such as the ones defined above.

2.6 Synthesis ofN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide(42)

4-Methyl-1,2,3-thiadiazole-5-carboxylic acid (0.105 g, 1.43 eq.) wasrefluxed in SOCl₂ (4 ml) for 2 h. Excess SOCl₂ was evaporated in vacuoand pyridine (3 ml) was added to the resulting residue. The obtainedmixture was stirred for 10 min,2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]-benzo[1,2-d]imidazol-6-aminehydrobromide (0.15 g, 0.51 mmol) was added and stirring was continuedovernight. Water (25 ml) was then added and the resulting suspension wasstirred for 1 h. The obtained precipitate was filtered off, washed withwater, dried and recrystallized from ethanol (with activated carbon) toobtain a pure solid (90 mg, 52% yield). ¹H NMR (400 MHz, DMSO+CCl₄):2.96 (3H, s, CH₃), 7.33 (2H, s, CH-benzimidazole), 12.78 (2H, s, NH).

2.7 General Procedure 4

V (1-1.5 eq.) was added to a suspension of compound 65 (1 mmol) in DCE(1,2-dichloroethene) (15 ml) and the mixture was stirred for 1 h. Thensodiumtriacetoxyborohydride (2 eq.), and acetic acid (0.5-2 ml) wereadded and the reaction mixture was stirred for 2 days. After completionof the reaction, the reaction solution was subjected, where necessary,to after-treatments such as the ones defined above

2.8 Synthesis ofN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(ethylamino)benzamide(77)

Acetaldehyde (0.013 ml, 1.1 eq.) was added to a suspension of compound65 (0.07 g, 0.21 mmol) in DCE (15 ml) and the mixture was stirred for 1h. Then sodiumtriacetoxyborohydride (0.089 g, 2 eq.) and acetic acid(0.3 ml) were added and the reaction mixture was stirred for 2 days. Themixture was then neutralized with an aqueous 10% sodium hydrogencarbonate solution and extracted with dichloromethane. The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by siliga gel flash columnchromatography (CHCl₃/EtOH=80:1+1 drop of HOAc) to obtain the pureproduct (20.3 mg, 39% yield). ¹H NMR (400 MHz, DMSO-d₆): 1.24 (3H, t,CH₃), 3.16 (2H, q, CH₂), 6.29 (1H, s, NH), 6.57 (2H, d, CH-arom.), 7.32(2H, s, CH-benzimidazole), 7.93 (2H, d, CH-arom.), 11.48 (1H, s, NH),12.40 (1H, s, NH)

3. Alternative Procedures for the Synthesis of Final Compounds 3.1Synthesis ofN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(2,3-dihydrobenzofuran-5-yl)thiophene-3-carboxamide(38)

Compound 29 (0.1 g, 0.2486 mmol) and (2,3-dihydrobenzofuran-5-yl)boronicacid (0.612 g, 1.5 eq) were suspended in DME (1,2-dimethoxyethane).Tetrakis(triphenylphosphine)-palladium(0) (0.03 g, 0.2 eq) and anaqueous 2M Na₂CO₃ solution (0.5 ml, 4 eq.) were added. The reactionmixture was stirred 20 h at 100° C., subsequently dissolved in ethylacetate and washed twice with water. The organic layer was concentratedin vacuo, the residue dissolved in methanol and purified by preparativeHPLC to obtain the pure product (4 mg, 4% yield).

3.2 Synthesis ofN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)cyclohexanecarboxamide(80)

IV (0.06 g, 0.2 mmol) was refluxed in chloroform withcyclohexanecarbonyl chloride (32 μl, 1.1 eq.) in the presence of DIPEA(0.1 ml, 0.57 eq.) during 2 days. Subsequently, the solvent wasevaporated and the residue was purified by silica gel flash columnchromatography (eluent: ethyl acetate) to obtain the pure product (0.04g, 61% yield). ¹H-NMR (400 MHz, DMSO-d6): 1.26-1.35 (5H, m, CH2),1.38-1.42 (1H, m, CH2), 1.51-1.86 (4H, m, CH2), 3.07-3.45 (1H, m, CH),7.18 (1H, s, CH-arom.), 7.31 (1H, s, Ch-arom.), 11.36 (1H, s, NH), 12.11(1H, s, NH).

3.3 Synthesis of4-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide(60)

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-nitrobenzamide(0.32 g, 0.88 mmol) was suspended in ethanol (20 ml), hydrazine hydrate(0.3 ml) and Pd/C (0.16 g), were added to the suspension and the mixturewas refluxed during 1.5 h. The catalyst was then filtered off; thesolution was evaporated in vacuum till dryness. The residue was washedwith water to obtain the pure product (0.23 g, 79% yield). NMR ¹H (400MHz, DMSO-d₆): 5.68 (2H, s, CH-arom.), 6.68 (2H, d, CH-arom.), 7.24 (2H,s, NH₂), 7.86 (2H, d, CH-arom.), 11.37 (1H, s, NH), 12.31 (1H, s, NH).

4. Synthesis of Intermediates 4.1 Synthesis of ethyl2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxylate

To a solution of Ethyl 2-aminothiazole-4-carboxylate (12 g, 70 mmol, 1eq.) in dry THF (300 ml) was added DIPEA (250 ml, 209 mmol, 3 eq.). Asolution of 2-(Trifluoromethoxy)-benzoyl chloride (19 g, 84 mmol, 1.2eq.) in THF (50 ml) was then added dropwise at 0° C. The reactionmixture was stirred for 24 h at rt. Water (50 ml) was then added and THFwas removed under reduced pressure. The obtained residue was extractedwith DCM (dichloromethane). The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel (PE/EtOAc 80:20).The product was obtained as a white solid (12 g, 33 mmol, 48% yield). ¹HNMR (DMSO-d₆): 1.28-0.133 (3H, t, CH₃), 4.26-4.33 (2H, q, CH₂),7.51-7.57 (2H, m, CH-arom.), 7.68-7.74 (1H, m, CH-arom.), 7.78-7.81 (1H,dd, CH-arom.), 8.14 (1H, s, CH-thiazole), 13.11 (1H, s, NH).

4.2 Synthesis of 2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxylicacid

Ethyl 2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxylate (10 g, 28mmol, 1 eq.) was dissolved in THF (20 ml) and an aqueous 2M NaOHsolution (110 ml) was added at rt. The reaction mixture was stirred for24 h at rt. THF was then removed under reduced pressure. The residualaqueous phase was acidified to pH=1-2 using 15% aqueous HCl. Theprecipitate was collected by filtration, washed with water and dried.The product was obtained as a white solid (10.4 g, 31 mmol, yield >90%).¹H NMR (DMSO-d₆): 7.51-7.57 (2H, m, CH-arom.), 7.68-7.74 (1H, m,CH-arom.), 7.78-7.81 (1H, dd, CH-arom.), 8.06 (1H, s, CH-thiazole),13.01 (1H, s, NH).

4.3 Synthesis of ethyl2-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)amino)thiazole-4-carboxylate

Ethyl 2-(diaminomethyleneamino)thiazole-4-carboxylate (2 g, 9,3 mmol, 1eq.) was dissolved in EtOH (200 ml) and 1,1,1-trifluoropentane-2,4-dione(1.2 ml, 9.3 mmol, 1 eq.) was added. The reaction mixture was stirredunder reflux for 3.5 h. EtOH was then partly removed under reducedpressure until a precipitate was formed. The precipitate was collectedby filtration, washed with EtOH and dried. The product was obtained as alight yellow solid (2.2 g, 6.6 mmol, 71% yield). ¹H NMR (DMSO-d₆):1.28-1.33 (3H, t, CH₃), 2.58 (3H, s, CH₃), 4.25-4.32 (2H, q, CH₂), 7.45(1H, s, CH-pyrimidine), 8.04 (1H, s, CH-thiazole), 12.39 (1H, s, NH).

4.4 Synthesis of2-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)amino)thiazole-4-carboxylicacid

Ethyl2-(4-methyl-6-(trifluoromethyl)pyrimidin-2-ylamino)thiazole-4-carboxylate(2.18 g, 6.56 mmol, 1 eq.) and LiOH (550 mg, 13.1 mmol, 2 eq.) weredissolved in a mixture of MeOH and water (52 ml:18 ml). The reactionmixture was stirred at room temprature for 2 h. The reaction mixture wasthen acidified to pH=2 using an aqueous 10% HCl solution. MeOH was thenremoved under reduced pressure. The precipitate formed was collected byfiltration to afford the product as a light yellow solid (2 g, 6.5 mmol,99% yield). ¹H NMR (DMSO-d6): 2.64 (3H, s, CH₃), 7.50 (1H, s,CH-pyrimidine), 8.03 (1H, s, CH-thiazole), 12.39 (1H, s, NH).

4.5 Synthesis of ethyl2-((2,6-dimethoxypyrimidin-4-yl)amino)thiazole-5-carboxylate

1-(2,6-dimethoxypyrimidin-4-yl)thiourea (6.133 g, 28.626 mmol) wassuspended in dry DMF. The bromo pyruvate (6.699 g, 34.351 mmol) wasdissolved in dry DMF and added dropwise to the mixture. The suspensioncleared off and was stirred for 2 h at rt. The mixture was concentratedin vacuo to obtain the product as a yellowish solid (12.9 g,yield: >100%). LC/MS [M+H]⁻: 310.96

4.6 Synthesis of2-((2,6-dimethoxypyrimidin-4-yl)amino)thiazole-5-carboxylic acid

ethyl 2-((2,6-dimethoxypyrimidin-4-yl)amino)thiazole-5-carboxylate (9.0g, 29 mmol) was suspended in EtOH (100 ml) and 2N NaOH (50 ml) was addedand the mixture was stirred for 4 h at it A precipitate formed. Further2N NaOH (40 ml) was added and the reaction mixture was stirred for 16 hat rt. The mixture was concentrated in vacuo. Upon addition of HCl (2 N)a precipitate was formed, which was filtered off and washed with water.The precipitate was dried in vacuo to obtain 11.58 g (89% yield) of thepure product. LC/MS [M+H]⁺: 284,36

4.7 Synthesis of ethyl5-(2-(trifluoromethoxy)benzamido)-1,2,4-thiadiazole-3-carboxylate

2-(Trifluoromethoxy)benzoyl chloride (1.1 g, 6.5 mmol, 1 eq.) wasdissolved in THF (130 ml) and 2-(trifluoromethoxy)benzoyl chloride (1.5g, 6.5 mmol, 1 eq.) and DIPEA (1.1 ml, 6.5 mmol, 1 eq.) were added. Thereaction mixture was stirred at room temperature for 18 h. Subsequently,all volatiles were removed under reduced pressure. The obtained residuewas triturated with ice water. The precipitate formed was collected byfiltration and dried. The crude product was purified by flash columnchromatography on silica gel (DCM/MeOH 95:5). The product was obtainedas a light yellow solid (1.05 g, 2.9 mmol, 45% yield) and was used assuch further. LC/MS [M+H]⁺: 361.86; ¹H NMR (DMSO-d₆): 1.31-1.36 (3H, t,CH₃), 4.34-4.41 (2H, q, CH₂), 7.56-7.58 (2H, m, CH-aromat), 7.75-7.81(1H, m, CH-aromat), 7.88-7.92 (1H, dd, CH-aromat), 13.97 (1H, s, NH).

4.8 Synthesis of5-(2-(trifluoromethoxy)benzamido)-1,2,4-thiadiazole-3-carboxylic acid

Ethyl 5-(2-(trifluoromethoxy)benzamido)-1,2,4-thiadiazole-3-carboxylate(1 g, 2.9 mmol, 1 eq.) and LiOH (244 mg, 5.8 mmol, 2 eq.) were dissolvedin a mixture of EtOH and H₂O (3:1) (40 ml) and the reaction mixture wasstirred at room temperature for 2 h. The mixture was then acidified topH=5 using an aqueous 10% HCl solution. The reaction mixture was thenconcentrated in vacuo. After cooling with an ice-bath, a precipitateformed, which was filtered off, washed with water and dried in vacuo.The product was obtained as a white solid (638 mg, 1.9 mmol, 66% yield).LC/MS [M+H]⁺: 333.87

4.9 Synthesis of ethyl2-(2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxylate

2-Chloro-oxazole-4-carboxylic acid ethyl ester (1.5 g, 8.5 mmol, 1 eq.)and 2,3-Dihydro-1-benzofuran-5-ylboronic acid (2.1 g, 12.8 mmol, 1.5eq.) were suspended in DME (170 ml).Tetrakis(triphenylphosphine)palladium(0) (987 mg, 0.85 mmol, 0.1 eq.)and an aqueous 2M sodium carbonate solution (17.1 ml, 34.2 mmol, 4 eq.)were added. The reaction mixture was stirred at 90° C. for 6 h. DME wasthen removed under reduced pressure. The obtained residue was dissolvedinEtOAc and was washed three times with water. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The obtained crudeproduct was purified by flash column chromatography on silica gel(PE/EtOAc 9:1 to 8:2). The fractions containing the product werecollected and concentrated in vacuo. The product was obtained as ayellow oil (472 mg, Purity: ca. 50%). LC/MS [M+H]⁻: 259.10

4.10 Synthesis of 2-(2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxylicacid

To a solution of Ethyl2-(2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxylate (472 mg, 1.8 mmol, 1eq.) in a mixture of THF and H₂O (2:1; 15 ml) was added LiOH (402 mg,9.6 mmol, 5 eq.) at rt. The reaction mixture was stirred at rt for 18 h.The reaction mixture was then concentrated in vacuo and partitionedbetween water (50 ml) and Et₂O (50 ml). The aqueous layer was acidifiedto pH=2-3 with an aqueous 1 M HCl solution. The resulting aqueous layerwas extracted twice with EtOAc. The organic layer obtained from theextraction with EtOAc was dried over MgSO₄, filtered and concentrated invacuo. The product was obtained as a brown crystalline solid (168 mg,0.7 mmol, 40% yield). LC/MS [M+H]⁺: 231.87

4.11 Synthesis of ethyl2-(3-(2-(trifluoromethoxy)phenyl)ureido)thiazole-4-carboxylate

To a solution of ethyl 2-aminothiazole-4-carboxylate (1 g, 5.8 mmol, 1eq.) in dry DCM (20 ml) was added a mixture of1-isocyanato-2-(trifluoromethoxy)benzene (1.2 g, 5.8 mmol, 1 eq.) in dryDCM (10 ml). The reaction mixture was stirred at room temperature for 3h. The precipitate formed was collected by filtration, washed with DCMand dried. The product was obtained as a white solid (1.9 g, 5 mmol, 86%yield). LC/MS [M+H]⁺: 376.12

4.12 Synthesis of2-(3-(2-(trifluoromethoxy)phenyl)ureido)thiazole-4-carboxylic acid

To a solution of ethyl2-(3-(2-(trifluoromethoxy)phenyl)ureido)thiazole-4-carboxylate (1.5 g,4.11 mmol, 1 eq.) in dry dioxane (10 ml) was added dropwise an aqueous2M NaOH solution (2.3 ml, 4.5 mmol, 1.1 eq.) at 0° C. The reactionmixture was stirred at rt for 8 h. After addition of an aqueous 2M HClsolution (2.3 ml) a solid precipitated. The solid was collected byfiltration, washed with water and dried. The product was obtained as awhite solid (1.4 g, 3.9 mmol, 95% yield). LC/MS [M+H]⁺: 348.06

4.13 Synthesis of methyl3-(2-(trifluoromethoxy)benzamido)-1H-1,2,4-triazole-5-carboxylate

2-(trifluoromethoxy)benzoyl chloride (0.26 ml, 1.2 eq.) was addeddropwise to a suspension of methyl3-amino-1H-1,2,4-triazole-5-carboxylate (0.22 g, 1.4 mmol) in pyridine(3 ml). The reaction mixture was stirred at rt overnight. Then themixture was diluted with water (20 ml) and stirred for 30 min. Acolorless oil was formed. The Water/pyridine solution was decanted andthe residual oil was treated with hexane to obtain 0.167 g of acolorless precipitate, which was used in the subsequent synthesis stepswithout further characterization.

4.14 Synthesis of3-(2-(trifluoromethoxy)benzamido)-1H-1,2,4-triazole-5-carboxylic acid

To a solution of methyl3-(2-(trifluoromethoxy)benzamido)-1H-1,2,4-triazole-5-carboxylate (0.16g) in the mixture of ethanol, water and potassium hydroxide (15 ml/15ml/0.15 g) was refluxed for 15 min. Ethanol was subsequently removed.The resulting solution was diluted with water and neutralized with HCluntil pH=3. The colorless precipitate was filtered off and washed withwater to obtain 0.117 g of the pure product. NMR ¹H (400 MHz, DMSO-d₆):7.41 (1H, d, CH-arom.), 7.49 (1H, t, CH-arom.), 7.65 (1H, t, CH-arom.),7.73 (1H, d, CH-arom.), 12.29 (1H.s, NH), 12.98 (1H, s, OH), 14.03 (1H,s, NH).

4.15 Synthesis of ethyl 5-acetamido-1H-1,2,4-triazole-3-carboxylate

A suspension of ethyl 5-amino-1H-1,2,4-triazole-3-carboxylate in aceticanhydride was refluxed for 30 min. Excess acetic anhydride wasevaporated. Water was added to the residue and the mixture was stirredovernight. The colourless product was filtered off, washed with waterand dried to obtain 0.134 g (53% yield) of the product. ¹H-NMR (40 MHz,DMSO-d₆): 1.35 (3H. t. OCH₂CH₃), 2.12 (3H, s, COCH₃), 4.3 (2H, q,OCH₂CH₃), 11.71 (1H, s, NHCO), 13.74 (1H, s, NH-triazole).

4.16 Synthesis of 5-acetamido-1H-1,2,4-triazole-3-carboxylic acid

A solution of ethyl 5-acetamido-1H-1,2,4-triazole-3-carboxylate (0.13 g,0.66 mmol) in NaOH/H₂O (0.079 g/5 ml) was stirred for 6 h. The solutionwas then acidified with conc. HCl to pH=2 and the colorless precipitatewas filtered off and dried to give the pure product (0.076 g, 69%yield). ¹H-NMR (40 MHz, DMSO-d₆): 2.12 (3H,s, COCH₃), 11.65 (1H, s,NHCO), 13.67 (1H, s, NH-triazole).

4.17 Synthesis of(6-Amino-2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-5-yl)(1-methyl-1H-pyrrol-2-yl)methanone

The compound was synthesized by the aforementioned general synthesisprotocols 1, D and C as described above.

Other carboxylic acid derivatives were synthezised analogously to theaforemnetioned synthesis protocols, which are to be understood asexemplary synthesis protocols.

5. Alternative Procedures for the Synthesis of Final Compounds 5.1Synthesis of4-Amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-pyrrole-2-carboxamide(15B)

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-nitro-1H-pyrrole-2-carboxamide(XX) (110.0 mg, 0.313 mmol) was dissolved in 10 ml methanol andpalladium on carbon (10%/C, 53.33 mg, 0.501 mmol) was added. Thereaction flask was then purged with hydrogen and the reaction mixturewas stirred for 2 h under an hydrogen atmosphere. The reaction mixturewas filtered over celite and the filtrate was concentrated in vacuo. Thecrude solid was washed with water and dried. The product was obtained asa brown solid (28 mg, 0.09 mmol, 28% yield).

5.2 Synthesis of3-((2,2-Difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoicacid (18B)

To a solution of ethyl2-(2,3-dihydrobenzofuran-5-yl)oxazole-4-carboxylate (32 mg, 0.085 mmol)in 6 ml THF/H₂O (1:1), Lithiumhydroxid monohydrate (56% LiOH, 25 mg,0.597 mmol) was added at room temperature The reaction mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated in vacuo and the aqueous layer was acidified to pH 2-3 withan aqueous 1 mol/1 hydrochlorid acid solution. The resulting solid wasfiltered off and dried. The product was obtained as a bright brown solid(14 mg, 0.04 mmol, 46% yield).

5.3 Synthesis ofN-(2,2-Difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1-methyl-1H-pyrrole-2-carboxamide(20B)

A suspension of(6-amino-2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-5-yl)(1-methyl-1H-pyrrol-2-yl)methanone(37.82 mg, 0.118 mmol) in 3 ml xylene and 1 ml DMF was refluxed for 4 h.The reaction mixture was lyophilized. The crude product was purified bypreparative TLC (DCM:MeOH 9:1) (PLC silica gel 60 F₂₅₄, 1 mm). Thehighest spot was isolated and purified by a second preparative TLC withthe same conditions as described above. The product was obtained as abeige solid (6 mg, 0.02 mmol, 16% yield).

6. Analysis of Synthesis Products

Analytical LC/ESI-MS parameters: Waters 2700 Autosampler. 1× Waters 1525Multisolvent Delivery System 5 μL sample loop. Column, Phenomenex Onyx™Monolythic C18 50.2 mm, with stainless steel 2 μm prefilter. Eluent A,H₂O+0.1% HCOOH; eluent B, MeCN. Gradient, 5% B to 100% B within 3.80min, then isocratic for 0.20 min, then back to 5% B within 0.07 min,then isocratic for 0.23 min; flow, 0.6 mL/min and 1.2 mL/min. WatersMicromass ZQ single quadrupol mass spectrometer with electrospraysource. MS method, MS4_15minPM-80-800-35V; positive/negative ion modescanning, m/z 80-800 or 80-900 in 1 s; capillary voltage, 3.50 kV; conevoltage, 35 V; multiplier voltage, 650 V; probe and desolvation gastemperature, 120° C. and 300° C., respectively. Waters 2487 Dual λAbsorbance Detector set to 254 nm. Software: Waters Masslynx V 4.0.

7. Exemplary Compounds of the Present Invention

TABLE 1 Exemplary compounds. The symbols in the columns “CK1 deltaAssay” and “CK1 epsilon Assay” have the following meanings: +++: IC₅₀ <200 nM, ++: IC₅₀ 200-1000 nM, +: IC₅₀ > 1 μM, each determined accordingto the kinase assays as described herein below. The symbols in thecolumn “HH Assay” have the following meanings: +++: IC₅₀ ≦ 500 nM, ++:IC₅₀ > 500-1000 nM, +: IC₅₀ 1-15 μM, each determined according to theHedgehog reporter assay as described herein below. The symbols in thecolumn “Wnt Assay” have the following meanings: +++: IC₅₀ < 5 μM, ++:IC₅₀ 5-20 μM, each determined according to the Wnt reporter assay asdescribed herein below. The indications in the column “Generalprocedure/aftertreatment” refers to the protocols as described above.CK1 CK1 General delta epsiplon HH Wnt procedure/ No. Structure AssayAssay Assay Assay [M + H]⁺ aftertreatment 1

+++ +++ + +++ 527.85 1 A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxamide 2

+++ ++ + 415.89 1 A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1-(4-fluorophenyl)-5-methyl-1H- pyrazole-4-carboxamide3

+++ ++ +++ 442.88 1 A, FN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,3-dihydrobenzofuran-5- yl)thiazole-4-carboxamide 4

++ ++ 401.05 1 E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-phenylthiazole-4-carboxamide 5

+ + 469.00 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-4- carboxamide 6

+ + 468.76 1 A, F 2-(2,3-dichlorophenyl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiazole-4-carboxamide 7

+ + + 334.74 1 A, F 3-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]imidazol-6-yl)pyrazine-2-carboxamide8

++ ++ 477.89 1 A 2-(4-chlorobenzamido)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)thiazole-4-carboxamide9

+ + 454.02 1 A, F 2-cinnamamido-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)oxazole- 4-carboxamide10

++ + 417.88 1 F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(furan-2-carboxamido)oxazole-4- carboxamide 11

+++ +++ 434.03 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(furan-2-carboxamido)thiazole-4-carboxamide 12

++ + 457.94 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2-methoxybenzamido)oxazole-4- carboxamide 14

+ + 479.80 1 A, B 1-(3,4-dichlorophenyl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3,5-dimethyl-1H-pyrazole-4-carboxamide 15

+ + 411.8 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4- carboxamide 16

++ ++ 451.88 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1-phenyl-3-(trifluoromethyl)-1H- pyrazole-4-carboxamide17

+++ +++ 528.91 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(2-(trifluoromethoxy)benzamido)-1,2,4- thiadiazole-3-carboxamide 18

+++ ++ 320.11 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)isonicotinamide 19

+++ +++ 539.8 1 A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,5-dimethoxyphenylsulfonamido)thiazole-4-carboxamide 20

+++ ++ 323.95 2 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiophene-3- carboxamide 21

+++ +++ 444.83 1 D, A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(isonicotinamido)thiazole-4- carboxamide 22

++ + 414.73 1 D, B 2-amino-6-bromo-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)pyrazine-2-carboxamide23

+ + 499.86 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-((4-(trifluoromethoxy)phenyl)amino)thiazole-4-carboxamide 24

++ ++ 393.70 1 A, D N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-morpholinooxazole-4-carboxamide 25

+ + 499.84 1 F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-((4-methyl-6-(trifluoromethyl)pyrimidin-2-yl)amino)thiazole-4-carboxamide 26

+++ +++ 542.97 1 A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(3-(2-(trifluoromethoxy)phenyl)ureido)thiazole-4-carboxamide 27

+ + + 319.71 1 A N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)pyrazine-2- carboxamide 28

++ ++ 351.81 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole-6-yl)-2,5-dimethylthiophene-3- carboxamide 29

+++ +++ 403.64 1 A, E 5-bromo-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole-6-yl)-thiophene-3-carboxamide 30

+++ +++ 368.74 1 A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole-6-yl)-5-nitrothiophene-3-carboxamide 31

+++ ++ 373.90 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzo[b]thiophene-3- carboxamide 32

++ +++ 307.95 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)furan-3- carboxamide 33

+++ ++ 321.85 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-methylfuran- 3-carboxamide 34

+ + 335.86 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2,5-dimethylfuran-3- carboxamide 35

++ + 308.90 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-oxazole-4- carboxamide 36

++ + 470.78 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1-(3-fluorophenyl)-5-(trifluoromethyl)-1H-1,2,3-triazole-4-carboxamide 37

+++ ++ 410.40 1 A, EN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-morpholinothiazole-4-carboxamide 38

+++ ++ 441.77 see description of alternative proceduresN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(2,3-dihydrobenzofuran-5- yl)thiophene-3-carboxamide39

+ ++ 444.80 1 A, E 2-(benzo[d][1,3]dioxol-5-yl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)thiazole-4-carboxamide40

+ + 426.84 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,3-dihydrobenzofuan-5-yl)oxazole-4- carboxamide 41

+++ +++ 351.8 2 D, E, C 3-chloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide 42

+ + 339.81 3 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide 43

++ ++ 385.7 2 D, E, C 2,4-dichloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol- 6-yl)benzamide 44

++ ++ 324.8 3 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiazole-4- carboxamide 45

++ ++ 323.8 2 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiophene-2- carboxamide 46

++ ++ 347.8 2 D, E, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-methoxybenzamide 47

++ + 401.7 2 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2- (trifluoromethoxy)benzamide 48

+++ ++ 511.7 1 D.E, B, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2- (trifluoromethoxy)benzamido)oxazole-5-carboxamide49

+++ +++ 317.9 2 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide 50

+ 398.8 3 D, G, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-methyl-3- phenylisoxazole-4-carboxamide 51

+++ ++ 496.02 1 D, E, C 3-(2,4-dichlorobenzamido)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-1,2,4-triazole-5-carboxamide 52

+++ ++ 512.31 1 D, E, cN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(2-(trifluoromethoxy)benzamido)-1H-1,2,4-triazole-5-carboxamide 54

++ + 353.8 2 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2,6- difluorobenzamide 55

++ ++ 402.40 1 2-bromo-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)thiazole-4-carboxamide56

+++ +++ +++ +++ 347.8 2 DN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide 57

+++ +++ 478.7 1 D, E 5-(3-chlorobenzamido-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1,2,4-thiazole-3-carboxamide 58

++ 363.21 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-nitrobenzamide 59

+ 369.24 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)quinoline-2-carboxamide 60

+++ 332.9 see description of alternative procedures4-amino-N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide 61

+ + 487.14 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(4-nitrobenzamido)-1H-1,2,4-triazole-5- carboxamide62

+++ 396.61 1 D, F, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-sulfamoylbenzamide 63

++ 368.73 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-nitrothiophene-2-carboxamide 64

+ 357.72 1 A, B 3-chloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiophene-2-carboxamide 65

+++ 362.78 1 A, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-nitrobenzamide 66

+++ 386.45 2 D, B, FN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(trifluoromethyl)benzamide 67

+ 318.43 2 D N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)picolinamide 68

++ + 331.85 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-methylbenzamide 69

+++ ++ 473.76 1 D, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(4-methoxybenzamido)thiazole-4- carboxamide 70

+++ 336.22 2 D, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-fluorobenzamide 71

++ 308.93 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)oxazole-5-carboxamide 72

++ 308.82 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)isoxazole-5-carboxamide 73

+ 307.82 1 D, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-pyrazole-3-carboxamide 74

++ 388.9 4 G, C 4-(diethylamino)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide 75

+++ 360.9 4 G, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(dimethylamino)benzamide 76

+++ 422.8 4 G, C 4-(benzylamino)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide 77

+++ 360.9 4 G, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(ethylamino)benzamide 78

+++ 318.8 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)nicotinamide 79

++ ++ 338.81 see description of alternative procedures2-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl) thiophene-3-carboxamide 80

+++ 323.9 see description of alternative proceduresN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)cyclohexamecarboxamide 81

+++ 406.7 1 E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(thiophen-3-yl)thiazole-4-carboxamide 82

+++ 459.2 1 D, E, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazole-4-carboxamide 83

+++ +++ 402.77 1 D, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-sulfamoylthiophene-3-carboxamide 84

+ + 308.89 1 A, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-1,2,4-triazole-3-carboxamide 85

++ ++ 401.76 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(methylsulfonyl)thiophene-2- carboxamide 86

+ + 367.74 1 A, B 5-chloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)-2-hydroxybenzamide 87

+++ ++ 332.88 1 A, D 3-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide 88

+++ +++ 351.78 1 D, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-nitro-1H-pyrrole-2-carboxamide 89

++ ++ 458.8 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(4-methylbenzamido)-1,2,4- thiadiazole-3-carboxamide90

+ + 474.7 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(4-methoxybenzamido)-1,2,4- thiadiazole-3-carboxamide91

+++ +++ 478.7 1 D, E 5-(4-chlorobenzamido-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1,2,4-thiazole-3-carboxamide 92

+++ +++ 462.8 1 D, EN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(4-fluorobenzamido)-1,2,4- thiadiazole-3-carboxamide93

+ 360.8 1 D, G, E 4-cyano-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2- fluorobenzamide 94

+++ 378.8 1 D, G, EN¹-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-fluoroterephthalamide 95

+ + 365.8 1 E 3-acetamido-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-1,2,4-triazole-5-carboxamide 96

+ + 308.9 1 E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-1,2,4-triazole-5- carboxamide 97

++ ++ 541.92 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(1-(thieno[3,2-d]pyrimidin-4-yl)piperidin-4- yl)thiazole-4-carboxamide98

++ + 570.27 1 A, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(3-(2-morpholinoethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)thiazole-4-carboxamide 99

+ + 477.84 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-((2,6-dimethoxypyrimidin-4-yl)amino)thiazole-5-carboxamide 100

+++ 397.13 1 A, B, FN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-sulfamoylbenzamide 101

+++ 385.75 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-sulfamoyl-1H-pyrrole-2-carboxamide 102

+++ +++ ++ 360.91 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(dimethylamino)benzamide 103

++ 307.87 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-imidazole-4-carboxamide 104

+++ +++ 348.87 1 D, B 4-acetyl-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-pyrrole-2-carboxamide 105

+++ +++ 375.73 1 D, B methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]imidazol-6-yl)carbamoyl)benzoate 106

+ 351.78 1 D, E 4-chloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol- 6-yl)benzamide 107

+ 331.84 2 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-methylbenzamide 108

+++ 410.74 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(methylsulfonamido)benzamide 109

++ 385.72 2 A, B 3,4-dichloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol- 6-yl)benzamide 110

++ 333.85 1 A, B 6-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)nicotinamide 111

+++ +++ 360.85 1 A, F N¹-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)terephthalamide 112

+++ 397.77 1 A, F N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-6-sulfamoylnicotinamide 113

+++ 333.85 1 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)-3-hydroxybenzamide114

+++ 359.82 1 D, F 3-acetyl-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide 115

++ 373.84 1 D, F 4-(tert-butyl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide 116

+++ 342.85 1 D, E 3-cyano-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide 117

+++ +++ 467.03 1 D, EN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(morpholinosulfonyl)benzamide 118

+++ +++ 385.79 1 D, A, EN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H-tetrazol-5-yl)benzamide 119

++ 335.86 1 D, F N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-fluorobenzamide 120

++ 401.73 2 A, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(trifluoromethoxy)benzamide 121

+++ 384.98 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(difluoromethoxy)benzamide 122

+++ +++ 386.89 1 D, BN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(pyrrolidin-1-yl)benzamide 123

+++ +++ 348.76 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5- methoxynicotinamide124

+++ +++ 348.85 1 D, EN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-methoxyisonicotinamide 125

+++ + 361.89 1 D N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(dimethylamino)isonicotinamide 126

+++ 400.79 1 A, B 4-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(trifluoromethyl)benzamide 127

++ 350.78 1 A, B 4-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3- fluorobenzamide 128

+++ 400.81 1 D, E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(piperidin-1-yl)benzamide 129

++ + 462.74 1 D, E 3-(chlorobenzamido)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-1,2,4-triazole-5-carboxamide 130

+++ +++ +++ 412.36 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)benzamide 131

+++ 428.35 1 D, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzamide 132

+++ 442.39 1 D, B 3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]imidazol-6-yl)benzamide133

+++ +++ 426.12 2 D, C(S)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(6-methoxymaphthalen-2- yl)propanamide 134

+++ +++ 423.01 1 E N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(4-methyl-1,2,3-thiadiazol-5-yl)thiazole-4-carboxamide 135

+++ +++ 408.00 1 D, E, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-[2,4-bithiazole]-4-carboxamide 136

+++ ++ 391.02 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(thiophen-2-yl)oxazole-4-carboxamide 137

+++ +++ ++ +++ 400.1 1 D, E, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(5-methyl-1,2,4-oxadiazol-3- yl)benzamide 138

+++ +++ ++ 391.02 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide 139

+++ 483.14 1 D, E, B ethyl 1-(3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)phenyl)-2,5-dimethyl-1H-pyrrole-3- carboxylate 140

+++ +++ ++ +++ 384.10 1 D, E, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H-imidazol-2-yl)benzamide 141

+++ +++ 406.03 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)thiazole-4- carboxamide 142

+++ + 384.1 1 D, E, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(1H-pyrazol-1-yl)benzamide 143

++ ++ 375.05 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(furan-2-yl)isoxazole-3-carboxamide 144

+++ + 403.09 1 D, E, CN-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide 145

+ 323.06 1 D, E, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-methylisoxazole-3- carboxamide 146

+ 336.09 1 D, E, B N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1,5-dimethyl-1H-pyrazole- 3-carboxamide 147

+++ +++ ++ 426.10 1 D, C 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]imidazol-6-yl)-benzamide148

+++ +++ +++ 400.09 1 D, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(5-methyl-1H-tetrazol-1-yl)benzamide 149

+++ +++ + ++ 386.08 1 D, C N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H-tetrazol-1-yl)benzamide

8. Further Exemplary Compounds of the Present Invention

TABLE 2 Further Exemplary compounds. The symbols in the columns have thesame meaning as in above Table 1. CK1 CK1 General delta epsilon HH WNTprocedure/ No. Structure Assay Assay Assay Assay [M + H]⁺ aftertreatment  1B

+++ +++ +++ 378.0  1 D, E  2B

+++ +++ 401.0  1 D, E  3B

+++ +++ ++ 362.0  1 D, E  4B

+++ 385.1  1 D, E  5B

+++ + 384.0  1 D, E, B, F  6B

+++ +++ ++ 391.02 1 E  7B

+++ + 404.0  1 D, E  8B

+++ +++ 366.0  1 D, E, B  9B

+++ +++ +++ 363.0  3 A, B 10B

+++ 451.00 1 D, E 11B

+++ + 407.00 1 E 12B

+++ 419.03 1 E 13B

+++ 322.07 1 D, E 14B

+++ 420.1  1 D, E, B 15B

+++ ++ 321.9  see Example 5.1 16B

+++ + 390.8  1 E, B 17B

+++ ++ 435.01 1 E, B 18B

++ ++ 361.9  see Example 5.2 19B

++ 485.03 1 E 20B

++ + 321.0  see Example 5.3 21B

++ 394.0  1 D, E 22B

+++ 386.07 1 D, C 23B

+++ 401.0  1 D, E 24B

++ 349.0  1 D, E or F 25B

+++ 404.0  1 D, E, F 26B

+ 349.0  1 D, E, F

9. NMR Data for Exemplary Compounds of the Present Invention

4: NMR ¹H (400 MHz, CDCl₃): 7.12 (1H, s, CH-benzimidazole), 7.24 (1H, s,CH-benzimidazole), 7.47 (3H, m, CH-arom.), 7.90 (2H, m, CH-arom.), 8.29(1H, s, CH-thiazole), 10.62 (1H, s, NH), 11.23 (1H, s, NH)

17: ¹H NMR (400 MHz, DMSO-d6+CCl₄): 7.50 (2H, s, CH-benzimidaz.),7.57-7.63 (2H, m CH-arom.), 7.74-7.80 (1H, m, CH-arom.), 7.91-7.94 (1H,dd, CH-arom.), 12.36 (2H, s, NH).

44: ¹H NMR (400 MHz, DMSO-d₆+CCl₄): 7.33 (2H, s, CH-benzimidazole), 8.64(1H, d, CH-thiazole), 9.20 (1H, d, CH-thiazole), 11.08 (1H, s, NH),12.40 (1H, s, NH).

50: ¹H NMR (400 MHz, DMSO-d₆): 2.67 (3H, s, CH₃), 7.31 (2H, s,CH-benzimidazole), 7.39-7.54 (3H, m, CH-arom.), 7.61-7.74 (2H, m,CH-arom.), 12.26 (2H, s, NH).

51: ¹H NMR (400 MHz, DMSO-d₆): 7.39 (2H, s, CH-arom.), 7.49 (1H, d,CH-arom.), 7.61 (1H, s, CH-arom.), 7.67 (1H, d, CH-arom.), 11.21 (1H, s,NH), 12.48 (2H, s, NH), 14.65 (1H, s, NH).

52: ¹H NMR (400 MHz, DMSO-d₆): 7.39 (2H, s, CH-arom.), 7.42 (1H, d,CH-arom.), 7.51 (1H, t, CH-arom.), 7.67 (1H, t, CH-arom.), 7.77 (1H, d,CH-arom.), 11.15 (1H, s, NH), 12.43 (2H, s, NH), 14.64 (1H, s, NH).

53: ¹H NMR (400 MHz, DMSO-d₆): 7.39 (2H, s, CH-arom.), 7.54 (1H, t,CH-arom.), 7.63 (1H, d, CH-arom.), 8.07 (1H, d, CH-arom.), 8.15 (1H, s,CH-arom.), 11.30 (1H, s, NH), 12.48 (2H, s, 2×NH), 14.51 (1H, s, NH).

54: ¹H NMR (400 MHz, DMSO-d₆): 7.13 (2H, t, CH-arom.), 7.33 (2H, s,CH-arom.), 7.52-7.59 (1H, m, CH-arom.), 12.40 (2H, s, NH).

55: ¹H NMR (400 MHz, DMSO-d₆+CCl₄): 7.32 (2H, s, CH-benzimidazole), 8.61(1H, s, CH-thiazole), 11.0-12.5 (2H, s, 2×NH).

56: ¹H NMR (400 MHz, DMSO-d₆): 3.89 (3H, s, CH₃), 7.13 (2H, d,CH-arom.), 7.34 (2H, s, CH-arom.), 7.41 (1H, t, CH-arom.), 7.71 (2H, s,CH-arom.), 12.13 (1H, s, NH), 12.37 (1H, s NH).

58: ¹H NMR (400 MHz, DMSO-d₆): 7.35 (2H, s, CH-arom.), 8.32 (2H, d,CH-arom.), 8.37 (2H, d, CH-arom.), 12.51 (2H, s, 2×NH).

59: ¹H NMR (400 MHz, DMSO-d₆): 7.39 (2H,s, CH-arom.), 7.74 (1H, t,CH-arom.), 7.89 (1H, t, CH-arom.), 8.08 (1H, d, CH-arom.), 8.27 (1H, d,CH-arom.), 8.32 (1H, d, CH-arom.), 8.61 (2H, d, CH-arom.), 11.32 (1H, s,NH), 12.53 (1H, s, NH).

61: ¹H NMR (400 MHz, DMSO-d₆): 7.42 (2H, s, CH-arom.), 8.34 (2H, d,CH-arom.), 8.39 (2H, d, CH-arom.), 11.41 (1H, s, NH), 12.51 (2H, s, NH),14.28 (1H, s, NH).

74: ¹H NMR (400 MHz, CDCl₃): 1.16 (6H, t, 2*CH₃), 3.39 (4H, q, 2×CH₂),6.44 (1H, s, CH-arom.), 6.57 (2H, d, CH-arom.), 7.07 (1H, s, CH-arom.),7.92 (2H, d, CH-arom.), 11.78 (1H, s, NH), 12.72 (1H, s, NH).

75: ¹H NMR (400 MHz, CDCl₃): 3.03 (6H, s, 2×CH₃), 6.50 (1H, s,CH-arom.), 6.60 (2H, d, CH-arom.), 7.09 (1H, s, CH-arom.), 7.91 (2H, d,CH-arom.), 11.71 (1H, s, NH), 12.32 (1H, s, NH)

76: ¹H NMR (400 MHz, DMSO-d₆): 4.36 (2H, d, CH₂), 6.59 (2H, d,CH-arom.), 6.94 (1H, t, CH-arom.), 7.19-7.35 (6H, m, CH-arom.), 7.89(2H, d, CH-arom.), 11.40 (1H, s, NH), 12.31 (1H, s, NH).

78: ¹H NMR (400 MHz, DMSO-d₆): 7.33 (2H, s, CH-arom.), 7.47-7.51 (1H, m,CH-arom.), 8.45 (1H, dt, CH-arom.), 8.72 (1H, d, CH-arom.), 9.23 (1H, d,CH-arom.), 12.40 (1H, s, NH).

81: ¹H NMR (400 MHz, DMSO-d₆+CCl₄): 7.32 (2H, s, CH-benzimidazole), 7.62(1H, m, CH-thien.), 7.75 (1H, m, CH-thien.), 8.27 (1H, m, CH-thien.),8.49 (1H, s, CH-thiazole), 11.29 (1H, s, NH), 12.42 (1H, s, NH).

89: ¹H NMR (400 MHz, DMSO-d₆): 2.44 (3H, s, CH₃), 7.39 (2H, dd,CH-arom), 7.42 (2H, s, CH-arom.), 8.10 (2H, dd, CH-arom.), 11.56-11.92(1H, s, NH), 12.32-12.64 (1H, s, NH), 13.70-14.94 (1H, s, NH).

90: ¹H NMR (400 MHz, DMSO-d₆): 3.89 (3H, s, CH3), 7.06 (2H. dd,CH-arom.), 7.36 (2H, s, CH-arom.), 8.20 (2H, dd, CH-arom.), 11.21-12.90(2H, s, NH), 13.37-13.94 (1H, s, NH).

91: ¹H NMR (400 MHz, DMSO-d₆): 7.36 (2H, s, CH-benzimidazole), 7.58 (2H,dd, CH-arom.), 8.22 (2H, dd, CH-arom.), 11.40-12.95 (3H, s, NH).

92: ¹H NMR (400 MHz, DMSO-d₆): 7.32 (2H, d, CH-arom.), 7.36 (2H, s,CH-arom.), 8.30 (2H, dd, CH-arom.), 11.22-12.80 (2H, s, NH), 13.17-14.49(1H, s, NH).

95: ¹H NMR (400 MHz, DMSO-d₆): 2.16 (3H, s, CH₃), 7.42 (2H, s,CH-arom.), 11.23 (1H, s, NH), 11.79 (1H, s, NH), 12.49 (1H, s, NH),14.05 (1H, s, NH).

96: ¹H NMR (400 MHz, DMSO-d₆): 7.41 (2H, s, CH-arom.), 8.64 (1H, s,CH-triazole), 12.80-13.20 (3H, s, 3×NH).

10. Determination of the Inhibitory Capacity; Casein Kinase Assays

The substrate CKltide (peptide HAAIGDDDDAYSITS-NH₂) was prepared in aconcentration of 20 μM in the freshly prepared Base Reaction Buffer (20mM Hepes (pH 7.5), 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA,0.1 mM Na₃VO₄, 2 mM DTT, 1% DMSO). The recombinant protein Casein kinase1 delta (CSKN1D) was added to the substrate solution in a concentrationof 5 nM and gently mixed. Dilution series in of compounds of the presentinvention in DMSO were added to the reaction mixture, followed after 20min by addition of a mixture of ATP and ³³P-ATP (specific activity 0.01μCi/μl final) to a final concentration of 10 μM. Reactions were carriedout at 25° C. for 120 min, followed by spotting the reactions onto P81ion exchange filter paper. Unbound phosphate was removed by washing ofthe filters in 0.75% phosphoric acid. After subtraction of thebackground, which was derived from control reactions containing inactiveenzyme, kinase activity data were expressed as percent remaining kinaseactivity in the test samples compared to vehicle (DMSO) reactions. IC₅₀values and curve fits were obtained using the program Prism® (Graph PadSoftware).

The above assay was also used to determine the inhibitory capacity ofthe compounds of the present invention on Casein Kinase 1 epsilon,wherein instead of CSKN1D, recombinant protein Casein kinase 1 epsilon(CSKN1E) was added to the substrate solution in a concentration of 30 nMand gently mixed.

The above tables land 2 provide an overview of the results of thecompounds in the CK1 delta and epsilon kinase Assays.

11. Determination of Proliferation Inhibition on a Panel of Cancer CellLines; Proliferation Assay

For the determination of the inhibitory capacity of compounds of thepresent invention (in the following: “test compound(s)”) on cell growth,cancer cells were seeded into microtitre plates, treated with differentconcentrations of test compound or left untreated, and after 72 h theprotein content was determined as an equivalent for the cell number.

Test compounds were dissolved in 100% DMSO and predilutions in cellculture medium were prepared with a final concentration of 0.1% DMSO inmedium. The cell culture medium for dilution of the test compounds,consecutive culturing of cell lines and usage during the assay was acell line specific medium as recommended by the cell line supplier andidentical for all three applications mentioned above. After a 24-hourpre-growth period of the seeded cancer cells, the test compoundcontaining media or medium containing 0.1% DMSO as control was added tothe cells. The cells were allowed to grow at 37° C. for 72 hours. Inaddition, all experiments contained a few plates with cells that wereprocessed for measurement immediately after the 24 hours recoveryperiod. These plates contained information about the cell number thatexisted before treatment, at time zero, and served to calculate thecytotoxicity and/or growth inhibitory effects.

After treatment, cells were precipitated by addition of 10% TCA(trichloracetic acid). Prior to fixation, the media was aspirated. Afteran hour of incubation at 4° C. the plates were washed twice with 400 μlof deionized water. Cells were then stained with 100 μl of a 0.08% wt/vSRB (sulforhodamine). The plates were allowed to sit for at least 30 minand washed six times with 1% acetic acid to remove unbound stainingagent. The plates were left to dry at room temperature and bound SRB wassolubilized with 100 μl of 10 mM Tris base. Measurement of opticaldensity was performed at 560 nm on a Victor 2 plate reader (PerkinElmer, Germany).

One common way to express the effect of an anticancer agent is tomeasure cell viability and survival in the presence of the test agent as% Treated/Control×100. The relationship between the viability and doseis called a dose response curve. Those dose response curves weredetermined by using algorithms developed by Oncolead GmbH & Co. KG,Munich, Germany, that can be compared to commercial applications, e.g.XLfit™ (ID Business Solutions Ltd., Guildford, UK) algorithm “205”. Thepotency of a given test compound to inhibit cell growth was specified asthe IC₅₀ value (drug concentration needed for 50% inhibition of cellgrowth).

The IC₅₀ of the compound of Example 56, determined as described above,with the following cell lines was in all cases 1 μM or lower: 22RV1(prostate), 5637 (bladder), 786O (kidney), A204 (muscle), A2780 (ovary),A375 (skin), A431 (skin), A549 (lung), A673 (muscle), ACHN (kidney),ASPC1 (pancreas), BT20 (breast), BXPC3 (pancreas), C33A (cervix), CAKI1(kidney), CALU6 (lung), CASKI (cervix), CLS439 (bladder), COLO205(colon), DLD1 (colon), DU145 (prostate), EFO21 (ovary), EJ28 (bladder),HCT116 (colon), HCT15 (colon), HEK293 (kidney), HELA (cervix), HEPG2(liver), HS729 (muscle), HS578T (breast), HT1080 (connective tissue),HT29 (colon), IMR90 (lung), IGROV1 (ovary), J82 (bladder), JAR(placenta), JEG3 (placenta), JIMT1 (breast), LOVO (colon), MCF7(breast), MDAMB435 (skin), MDAMB436 (breast), MDAMB468 (breast), MG63(bone), MHHES1 (bone), MIAPACA2 (pancreas), MT3 (breast), NCIH292(lung), NCIH358M (lung), NCIH460 (lung), NCIH82 (lung), OVCAR3 (ovary),OVCAR4 (ovary), PANC1 (pancreas), PANC1005 (pancreas), PC3 (prostate),PLCPRFS (liver), RD (muscle), RDES (bone), SAOS2 (bone), SF268 (brain),SF295 (brain), SKBR3 (breast), SKHEP1 (liver), SKLMS1 (uterus), SKMEL28(skin), SKMEL5 (skin), SKNAS (brain), SKNSH (brain), SNB75 (brain),SW620 (colon), T24 (bladder), TE671 (muscle), U2OS (bone), U87MG(brain). UMUC3 (bladder), SKOV3 (ovary), in the following cases 100 nMor lower: A2780 (ovary), A375 (skin), A673 (muscle), BXPC3 (pancreas),CALU6 (lung), EJ28 (bladder), HCT116 (colon), HCT15 (colon), JAR(placenta), LOVO (colon), MCF7 (breast), MDAMB435 (skin), MG63 (bone),MHHES1 (bone), NCIH358M (lung), PC3 (prostate), SF295 (brain), SKMELS(skin), SKNAS (brain).

12. Inhibition of Anchorage Independent Growth, Soft Agar ColonyFormation

To analyze anchorage-independent growth, cells were seeded in 12-wellplates in 0.4% select agar® on top of 0.5% bottom select agar®(Invitrogen) according to standard protocols. 8000 PANC1 cells wereseeded in 400 μl select agar and the compound according to the presentinvention or DMSO as control was added in a final volume of 400 μlgrowth medium to the top agar. Cultures were grown for 21 days at 37° C.in a humidified atmosphere of 5% CO₂. Fresh growth medium was addedagainst drying-out twice per week. Colony growth in soft agar cultureswas quantified using Colony Counter software (Microtech Nition).

Depending on the addition of Culture plates exhibit growth of cancercell colonies, wherein some colonies develop into macrocolonies having adiameter which is approximately ≧4 times larger than the median diameterover all cancer cell colonies (in said well). The inhibition of bothoverall colony formation (including macrocolony formation) andmacrocolony formation alone by compounds of the present invention wasdetermined, results are shown in FIG. 1. Macrocolonies of this cell lineare rare but highly clonogenic, tumor-initiating cells with highactivity of the Hedgehog signaling pathway. Inhibition of thosemacrocolonies in vitro can be interpreted to relate to cancer stem cellinhibition in tumor bearing patients (Eberl et al., EMBO Mol Med, 2011,4, 218-233).

Growth medium Stock solutions (sterilized, stored at 4° C.): 2× DMEM,GIBCO powder: 26.76 g DMEM powder (GIBCO, with 4.5 g/l Glucose), 7.4 gNaHCO3, 220 mg Sodium Pyruvate (Sigma, 11.0 mg/ml solution); dissolve inwater, adjust pH with 2M Hepes to 7.2; final volume 1 liter. 2×DMEM, PAApowder: 27 g DMEM powder (PAA Art. No. G0006.3010, with 4.5 g/l Glucose,with Sodium Pyruvate), 7.4 g NaHCO3; dissolve in water, adjust pH to6.8-7.5 with 1N HCl; final volume 1 liter.

Before usage, add 50 ml FBS and 5 ml PenStrep (100× stock) to 200 mlaliquot; store this 2× medium for maximum 6-8 weeks at 4° C.

2× stock solutions of 1% (bottom) and 0.8% (top) Select Agar: 1 g or 0.8g, respectively, Select Agar (Invitrogen, Art. No. 30391-023) in 100 mlwater (=1% or 0.8% final, respectively). Store at 4° C. until needed.

Bottom Agar (=0.5% agar final concentration): Melt “1% SelectAgar”-stock in microwave; cool down to 42° C. in a water bath; warm 2×DMEM to 37° C.; mix Select Agar and 2× DMEM solution 1:1 (avoidbubbles); plate 800 μl Agar/DMEM mix in each well; allow to cool andharden completely (room temperature)can be stored at 4° C. for up to 2weeks prior to use.

Top Agar (=0.4% agar final concentration, containing cells); Melt “0.8%Select Agar”-stock in microwave; cool down to 40° C. in a water bath;warm 2× DMEM to 37° C.; let bottom agar plates warm to room temperature(or warm in 37° C. incubator); mix Select Agar and 2× DMEM solution 1:1(avoid bubbles); aliquot Agar/DMEM mix in 15 ml tubes and store at 40°C.; Trypsinize cells and determine cell count; add 8000 cells per wellto Agar/DMEM mix; again mix by gently inverting tube and plate out;allow to cool and harden top agar in laminar flow (˜30 min; roomtemperature); pipette 400 μl medium (containing optional chemicalsubstances) onto top agar to prevent drying-out; Replace supernatant asappropriate (e.g. 2× per week).

13. Wnt Reporter Assay

The Wnt reporter assay was performed in stably transfected human HEK293cells. Wnt signaling was induced by administration of Wnt3a protein andread out by β-Lactamase mediated cleavage of CCF4-AM and subsequentfluorescent detection.

CellSensor LEF/TCF-bla FreeStyle 293F cells (invitrogen #K1677) containa beta-lactamase reporter gene under control of the β-catenin/LEF/TCFbinding elements stably integrated into FreeStyle 293F cells. This cellline can be used to detect antagonists of the Wnt/β-catenin signalingpathway when stimulated by mouse Wnt3a or LiCl. The detection ofbeta-lactamase is possible with LiveBLAzer FRET—B/G Loading Kit(invitrogen #K1095) with CCF4-AM as subtrate.

Culture Medium: DMEM Medium +10% dialyzed FBS (PAN 2102-P290310), +1%NEAA (PAA M11-003), +1% P/S (Penicillin/Streptomycin, PAA P11-010) +25mM HEPES (PAA S11-001), +5 μg/ml Blasticidin (PAA P05-017).

Assay Medium: Opti-MEM (Gibco 11058-021) +0.5% dialyzed FBS (PAN2102-P290310), +1% NEAA (PAA M11-003), +1% P/S (PAA P11-010), +10 mMHEPES (PAA S11-001), +1 mM Na-Pyruvate (PAA S11-003).

Cells (CellSensor LEF/TCF-bla FreeStyle 293F, invitrogen K1677) weresplit with Culture Medium to reach a confluence at the beginning of theassay of 80-90%.

At start of the assay, cells were harvested from culture and resuspendin assay medium at density of 0,66*10̂6 cells/ml. Subsequently, 60μ1 cellsuspension were pipetted in each well of a Poly-D-Lysine 96 well Plate(BD #354640, vertical rows are marked 1 through 12, horizontal lanes aremarked A through H),

1 2 3 4 5 6 7 8 9 10 11 12 A 120 μl Medium B 60 μl cells + 60 μl 60 μl60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl C 60 μl cellscells cells cells cells cells cells cells cells cells medium D medium E60 μl cells + 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60 μl 60μl 60 μl F 60 μl cells cells cells cells cells cells cells cells cellscells cells G medium H 120 μl Medium

Plates were subsequently incubated at 37° C. for at least 2 h.

To stimulate with Wnt3a, overnight prestimulation of Wnt signallingpathway with LiCl is necessary. Subsequently, an 8M aqueous LiClsolution was diluted 1:200 in assay medium, and 30 μl of said dilutedLiCl solution was plated into the appropriate wells (see below pipettingscheme). Plates were then incubated at 37° C. over night.

Subsequently, compounds and controls were prepared as follows: mWnt3a(R&D 1324-WN, dissolved in PBS+0.1% BSA to 40 μg/ml) was diluted 1:100in assay medium (=400 ng/ml). Compounds (Cpd) were diluted to aconcentration of 10 mM in DMSO to prepare dilution series in assaymedium (final concentrations 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM,0.03 μM and 0.01 μM), which were pipetted into the appropriate wells(see below pipetting scheme). For each dilution of each compound, 3replicates were tested. Final DMSO concentration was 0.3%.

LiCl and mWnt3a stimulated cells were used as High control (HC),unstimulated cells were used as low control, a blank was prepared fromcell free medium plus mWnt3a, and a functional control was prepared witha known Wnt inhibitor (e.g. PKF118-310), final concentrations were asabove.

Pipetting scheme:

Subsequently, the well was incubated for 5 h at 37° C.

At t=23 hours, FRET reagent mix (Loading Kit with CCF4-AM, LifeTechnologies #K1096) was prepared; per plate: 138 μl Solution B, 13.8 μlFRET-reagent, and 2300 μl Solution C. 24 μl FRET reagent mix were platedto each well, subsequently plates were incubated for at least 2 h in thedark (it is possible to incubate over night). Subsequently, plates weremeasured in the BMG FluorStar® plate reader at an emission waveltengthsof 460 and 520 nm and with an excitation wavelength of 405 nm.

To determine potential cytotoxicity of the compounds, plates werecentrifuge and the supernatant was discarded by dumping the plates.Subsequently, 100 μl Opti-MEM and 50 μl ViaLight (Lonza #LT07-321) LysisBuffer were added to each well, followed by incubation for 10 min atroom temperature (25° C.). Subsequently, 100 μl ViaLight reagent wereadded to each well, followed by incubation for 2 min at room temperature(25° C.) in the dark. Optionally, 200 μl of the obtained suspension weretransferred to a white 96 well plate. The luminescence was measured witha Tecan Ultra plate reader.

13. Hedgehog Reporter Assay

In order to investigate the potency of test compounds to inhibit theHedgehog signaling pathway, a Gli-Reporter assay was performed.

The “Gli Reporter—NIH3T3 Cell Line” contains the firefly luciferase geneunder the control of Gli responsive elements stably integrated intomurine NIH3T3 cells (cells purchased from Amsbio). The luciferaseexpression correlates with activation of the hedgehog signaling pathway.This cell line is validated for its response to stimulation with murineSonic Hedgehog and to treatment with inhibitors of the hedgehogsignaling pathway. A multiplexed viability assay was used todiscriminate inhibition on the pathway activity from cell toxicity.

Growth Medium: DMEM, 10% Calf Serum, 1% Penicillin/Streptomycin 500μg/ml Geneticin (G418 Stock 50 mg/ml).

Assay Medium: Opti-MEM® Reduced Serum Medium, 0.5% Calf Serum, 1%non-essential amino acids, 1 mM Na-pyruvate, 10 mM HEPES, 1%Penicillin/Streptomycin.

25.000 cells per well were seeded into a white 96 well plate in 100 μlgrowth medium and incubated over night at 37° C. and 5% CO₂. Afterremoving the supernatant the test compounds and controls (known GLIinhibitor, e.g. GANT-61) were added in different concentrations in afinal volume of 45 μl and incubated for 1 h at 37° C. and 5% CO₂. Forthe stimulation of the Hedgehog pathway 5 μl of 10 μg/ml concentratedmurine sonic hedgehog (SHH) was added to the cells. A finalconcentration of 1 μg/ml mSHH and 0.1% DMSO was reached per well. Afterincubation for 24 h at 37° C. the cells were investigated for viabilityand reporter activity.

Viability: For the determination of the viability of the treated cellsthe CellTiter-Fluor Kit from Promega was used. Essentially, onlyproteases of viable cells are able to cleave the cell-permeant substrateGly-Phe-AFCoumarin (GF-AFC). By this cleavage the fluorescent AFC is setfree and can be detected in a fluorescence reader. For this assay 10 μlof GF-AFC substrate (CellTiter-Fluor, Promega #G6082) was diluted in 2ml assay buffer from the CellTiter-Fluor Kit and 10 μl of this dilutionwas added per well to the cells and incubated for 30 min at 37° C. Thefluorescence was measured with excitation at 380-400 nm and emission at505 nm.

Reporter activity: The firefly luciferase reporter activity was detectedwith the ONE-Glo™ Luciferase Assay System from Promega. For this assay50 μl ONE-Glo luciferase reagent (Promega #E6120, contains cell lysisbuffer and luciferin) was added to each well and incubated at roomtemperature for 5 min. Luminescence was detected in a plate reader andserved as a degree for reporter activity.

1. A compound of the general formula (I) or a physiologically functionalderivative, solvate or salt thereof,

wherein R is independently selected from the group comprising H,halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy,—S—R′″, —SO—R′″, nitro, —N(R′″)₂, —NH(R′″), —NHCO(R′″), —CONH₂,—CONH(R′″), —CO(R′″), —COH, —COO(R′″), —COOH, —SO₂NH₂, —SO₂NH(R′″),—SO₂(R′″), and —NH—SO₂(R′″), wherein in the cases where said group R isC₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, or C₁₋₆-alkoxy, said groupR may be substituted with one or more substituents R″ independentlyselected from the group comprising H, halogen, OH, nitro, —NH₂,—N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂,—CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH, and—CN, and wherein R′″ is independently selected from the group comprisingH, C₁₋₆-alkyl, C₁₋₆-haloalkyl, aryl, heteroaryl, cycloalkyl andheterocyclyl; R^(N) is independently selected from the group comprisingH, alkyl, haloalkyl, OH, aryl, heteroaryl, cycloalkyl, heterocyclyl,—SO—R′″, —NH₂, —N(R′″)₂, —NH(R′″), —NHCO(R′″), —CONH₂, —CONH(R′″),—CO(R′″), —COH, —COO(R′″), —COOH, —SO₂NH₂, —SO₂NH(R′″), —SO₂(R′″), and—NH—SO₂(R′″), wherein R′″ is as defined above, wherein in the caseswhere said group R^(N) is alkyl, haloalkyl, aryl, heteroaryl,cycloalkyl, or heterocyclyl, said group R^(N) may be substituted withone or more substituents R′″ as defined above; A is independentlyselected from *—N(R^(a))CO—, *—CON(R^(a))—, *—SO₂N(R^(a))—, and*—N(R^(a))—SO₂—, wherein R^(a) is selected from H and C₁₋₄-alkyl, andwherein * specifies the point of attachment to X; X is independentlyselected from the group comprising aryl, cycloalkyl, aralkyl,heterocyclyl and heteroaryl, wherein said group X may be substitutedwith one or more R^(X) independently selected from the group comprisinghalogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy,aryl, heteroaryl, cycloalkyl, heterocyclyl, —S—C₁₋₆-alkyl,—S—C₁₋₆-haloalkyl, nitro, —NH₂, —N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl),—NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH,—COO(C₁₋₆-alkyl), —COOH, —SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl),—NH—SO₂(C₁₋₆-alkyl), C₃₋₆-cycloalkyl, and —CN; L is independently a bondor a linker group selected from the group comprising *—NHCO—, *—CONH—,*—NH—, *—N(C₁₋₄-alkyl)-, *—C═N(C₁₋₄-alkyl)-, *—NH—C₁₋₄-alkyl-,*—C₁₋₄-alkyl-NH—, *—NHCONH—, *—CO—, *−SO₂—, C₁₋₄-alkyl,*—C₁₋₂-alkyl-O—C₁₋₂-alkyl-, *—NHCO—CH═CH—, *—CH═CH—CONH—, *—SO₂NH—,*—NHSO₂—, and pyridinyl, wherein * specifies the point of attachment toX; and Y is independently selected from the group comprising H, alkyl,aryl, aralkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein saidgroup Y may optionally be substituted with one or more R^(Y)independently selected from the group comprising halogen, C₁₋₆-alkyl,C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, aryl, heteroaryl,cycloalkyl, heterocyclyl, —S—C₁₋₆-alkyl, —S—C₁₋₆-haloalkyl, nitro, —NH₂,—N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂,—CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH,—SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), —NH—SO₂(C₁₋₆-alkyl),C₁₋₆-alkyl-heterocyclyl, cycloalkyl and —CN.
 2. A compound according toclaim 1, which is a compound of the general formula (Ia) or aphysiologically functional derivative, solvate or salt thereof,

wherein X is independently selected from the group comprising aryl,cycloalkyl, aralkyl, heterocyclyl and heteroaryl, wherein said group Xmay be substituted with one or more R^(X) independently selected fromthe group comprising halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, aryl, heteroaryl, cycloalkyl,heterocyclyl, —S—C₁₋₆-alkyl, —S—C₁₋₆-haloalkyl, nitro, —NH₂,—N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂,—CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH,—SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), —NH—SO₂(C₁₋₆-alkyl),C₃₋₆-cycloalkyl, and —CN; L is independently a bond or a linker groupselected from the group comprising *—NHCO—, *—CONH—, *—NH—,*—N(C₁₋₄-alkyl)-, *—C═N(C₁₋₄-alkyl)-, *—NH—C₁₋₄-alkyl-,*—C₁₋₄-alkyl-NH—, *—NHCONH—, *—CO—, *—SO₂—, C₁₋₄-alkyl,*—C₁₋₂-alkyl-O—C₁₋₂-alkyl-, *—NHCO—CH═CH—, *—CH═CH—CONH—, *—SO₂NH—,*—NHSO₂—, and pyridinyl, wherein * specifies the point of attachment toX; and Y is independently selected from the group comprising H, alkyl,aryl, aralkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein saidgroup Y may optionally be substituted with one or more R^(Y)independently selected from the group comprising halogen, C₁₋₆-alkyl,C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, aryl, heteroaryl,cycloalkyl, heterocyclyl, —S—C₁₋₆-alkyl, —S—C₁₋₆-haloalkyl, nitro, —NH₂,—N(C₁₋₆-alkyl)₂, —NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂,—CONH(C₁₋₆-alkyl), —CO(C₁₋₆-alkyl), —COH, —COO(C₁₋₆-alkyl), —COOH,—SO₂NH₂, —SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), —NH—SO₂(C₁₋₆-alkyl),C₁₋₆-alkyl-heterocyclyl, cycloalkyl and —CN.
 3. The compound accordingto claim 1 or a physiologically functional derivative, solvate or saltthereof, wherein X is independently selected from the group comprisingaryl, aralkyl, cycloalkyl, heterocyclyl and heteroaryl, wherein saidgroup X may be substituted with one or more R^(X) independently selectedfrom the group comprising F, Cl, Br, I, C₁₋₆-alkyl, C₁₋₆-haloalkyl,C₁₋₆-haloalkoxy, OH, C₁₋₆-alkoxy, nitro, —NH₂, —N(C₁₋₆-alkyl)₂,—NH(C₁₋₆-alkyl), —NHCO(C₁₋₆-alkyl), —CONH₂, —CONH(C₁₋₆-alkyl), —SO₂NH₂,—SO₂NH(C₁₋₆-alkyl), —SO₂(C₁₋₆-alkyl), C₃₋₆-cycloalkyl,—NH—SO₂(C₁₋₆-alkyl), —COOH, —COO—C₁₋₆-alkyl, and —CN; L is independentlya bond or a linker group selected from the group comprising *—NHCO—,*—NH—, *—NHCH₂—, *—NHCONH—, *—NHCO—CH═CH—, *—NHSO₂—, *—SO₂—, andpyridinyl, wherein * specifies the point of attachment to X; and Y isindependently selected from the group comprising H, aryl, cycloalkyl,heterocyclyl and heteroaryl, wherein said group Y may optionally besubstituted with one or more R^(Y) independently selected from the groupcomprising F, Cl, Br, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-haloalkoxy,C₁₋₆-alkoxy, C₁₋₆-alkyl-morpholinyl, and nitro.
 4. The compoundaccording to claim 1 or a physiologically functional derivative, solvateor salt thereof, wherein X is independently selected from the groupcomprising 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl,1H-1,2,4-triazolyl, 1H-pyrazolyl, 1H-pyrrolyl, phenyl,benzo[b]thiophenyl, cyclohexyl, furyl, isoxazolyl, oxazolyl, imidazolyl,1H-pyrazolyl, pyrazinyl, pyridyl, quinolinyl, 1-(naphthalen-2-yl)ethyl,thiazolyl, benzyl and thiophenyl, wherein said group X may besubstituted with one or more R^(X) independently selected from the groupcomprising F, Cl, Br, methyl, tert-butyl, trifluoromethyl,trifluoromethoxy, difluoromethoxy, OH, acetyl, methylcarbamoyl, methoxy,nitro, —NH₂, —NEt₂, —NMe₂, —NHEt, —NHCOCH₃, —CONH₂, —SO₂NH₂, —SO₂Me,—NH—SO₂Me, —COOH, and —CN; L is independently a bond or a linker groupselected from the group comprising comprising *—NHCO—, *—NH—, *—NHCH₂—,*—NHCONH—, *—NHCO—CH═CH—, *-pyridinyl-, —SO₂—, and *—NHSO₂—, wherein *specifies the point of attachment to X; and Y is independently selectedfrom the group comprising H, phenyl, furyl, thiophenyl, pyridyl,pyrimidyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzofuranyl,benzo[d][1,3]dioxolyl, thieno[3,2-d]pyrimidinyl,2-oxo-2,3-dihydrobenzoimidazolyl, pyrrolidinyl, tetrazolyl, piperidinyl,pyrazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, pyrrolyl, imidazolyl,isoxazolyl, thiazolyl, thiomorpholinyl, and morpholinyl, wherein saidgroup Y may be substituted with one or two R^(Y) independently selectedfrom the group comprising F, Cl, methyl, isopropyl, tert-butyl,trifluoromethyl, trifluoromethoxy, methoxy, methylcarbamoyl,cyclopropyl, 2-morpholinoethyl, and nitro.
 5. The compound according toclaim 1 or a physiologically functional derivative, solvate or saltthereof, wherein X is independently selected from the group comprising

wherein * specifies the point of attachment to the central moiety, #specifies the point of attachment to L and wherein the group X may besubstituted with one or more R^(X); L is independently a bond or alinker group selected from the group comprising *—NHCO—, *—NH—,*—NHCH₂—, *—NHCONH—, *—NHCO—CH═CH—, *-pyridinyl-, —SO₂—, and *—NHSO₂—,wherein * specifies the point of attachment to X; Y is independently Hor selected from the group comprising

wherein * specifies the point of attachment to L and wherein the group Ymay be substituted with one or more R^(Y); or wherein X is selected fromthe group comprising

wherein * specifies the point of attachment to the central moiety,wherein L is a bond, Y is H, and wherein the group X may be substitutedwith one or more R^(X); wherein each R^(Y) is independently selectedfrom the group comprising F, Cl, methyl, isopropyl, tert-butyl,trifluoromethyl, trifluoromethoxy, methoxy, methylcarbamoyl,cyclopropyl, 2-morpholinoethyl, and nitro; and wherein each R^(X) isindependently selected from the group comprising F, Cl, Br, methyl,tert-butyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, OH,acetyl, methylcarbamoyl, methoxy, nitro, —NH₂, —NEt₂, —NMe₂, —NHEt,—NHCOCH₃, —CONH₂, —SO₂NH₂, —SO₂Me, —NH—SO₂Me, —COOH and —CN.
 6. Thecompound according to claim 1, wherein said compound is selected fromone of the following:

or a physiologically functional derivative, solvate or salt thereof. 7.The compound according to claim 1, wherein said compound is selectedfrom one of the following: No. Structure  1

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2-(trifluoromethoxy)benzamido)thiazole-4-carboxamide  2

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1-(4-fluorophenyl)-5-methyl-1H- pyrazole-4-carboxamide 3

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,3-dihydrobenzofuran-5- yl)thiazole-4-carboxamide 11

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(furan-2-carboxamido)thiazole-4-carboxamide  17

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(2-(trifluoromethoxy)benzamido)-1,2,4-thiadiazole-3-carboxamide  18

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)isonicotinamide  19

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,5-dimethoxyphenylsulfonamido)thiazole-4-carboxamide  20

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiophene-3-carboxamide  21

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(isonicotinamido)thiazole-4- carboxamide  26

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(3-(2-(trifluoromethoxy)phenyl)ureido)thiazole-4-carboxamide  29

5-bromo-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiophene-3-carboxamide  30

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-nitrothiophene-3-carboxamide  31

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzo[b]thiophene-3-carboxamide  33

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-methylfuran- 3-carboxamide  37

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-morpholinothiazole-4-carboxamide  38

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(2,3-dihydrobenzofuran-5-yl)thiophene-3-carboxamide  41

3-chloro-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide  48

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2- (trifluoromethoxy)benzamido)oxazole-5-carboxamide 49

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide  51

3-(2,4-dichlorobenzamido)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-1,2,4-triazole-5-carboxamide  52

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(2-(trifluoromethoxy)benzamido)-1H-1,2,4-triazole-5-carboxamide  56

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide  57

5-(3-chlorobenzamido)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1,2,4-thiadiazole-3- carboxamide 60

4-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)benzamide  62

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-sulfamoylbenzamide  65

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-nitrobenzamide  66

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(trifluoromethyl)benzamide  69

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(4-methoxybenzamido)thiazole-4-carboxamide  70

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-fluorobenzamide  75

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(dimethylamino)benzamide  76

4-(benzylamino)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6- yl)benzamide  77

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(ethylamino)benzamide  78

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)nicotinamide  80

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)cyclohexanecarboxamide  81

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(thiophen-3-yl)thiazole-4- carboxamide  82

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazole-4-carboxamide  83

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-sulfamoylthiophene-3- carboxamide  87

 88

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-nitro-1H- pyrrole-2-carboxamide  91

5-(4-chlorobenzamido)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1,2,4-thiadiazole-3-carboxamide  92

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(4-fluorobenzamido)-1,2,4- thiadiazole-3-carboxamide 94

N¹-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-fluoroterephthalamide 100

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5] benzo[1,2-d]imidazol-6-yl)-3-sulfamoylbenzamide 101

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-sulfamoyl-1H-pyrrole-2-carboxamide 102

N-(2,2-difluoro-5H-[1,3]dioxolo [4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(dimethylamino)benzamide 104

4-acetyl-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)- 1H-pyrrole-2-carboxamide 105

methyl 3-((2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate 108

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5] benzo[1,2-d]imidazol-6-yl)-3-(methylsulfonamido)benzamide 111

N¹-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)terephthalamide 112

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-6-sulfamoylnicotinamide 113

N-(2,2-difluoro-5H-[1,3]dioxolo [4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide 114

3-acetyl-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl) benzamide 116

3-cyano-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl) benzamide 117

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(morpholinosulfonyl)benzamide 118

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H-tetrazol-5-yl)benzamide 121

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(difluoromethoxy)benzamide 122

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(pyrrolidin-1- yl)benzamide 123

N-(2,2-difluoro-5H-[1,3]dioxolo [4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-methoxynicotinamide 124

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5] benzo[1,2-d]imidazol-6-yl)-2-methoxyisonicotinamide 125

N-(2,2-difluoro-5H-[1,3]dioxolo [4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(dimethylamino)isonicotinamide 126

4-amino-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3- (trifluoromethyl)benzamide 128

N-(2,2-difluoro-5H-[1,3]dioxolo [4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(piperidin-1-yl)benzamide 130

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(3,5- dimethyl-1H-pyrazol-1-yl)benzamide131

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(5-isopropyl-1,2,4- oxadiazol-3-yl)benzamide 132

3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]imidazol-6-yl)benzamide133

(S)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(6-methoxynaphthalen-2- yl)propanamide 134

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(4-methyl-1,2,3-thiadiazol-5-yl)thiazole-4-carboxamide 135

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-[2,4′-bithiazole]- 4-carboxamide 136

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(thiophen-2- yl)oxazole-4-carboxamide 137

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(5-methyl-1,2,4- oxadiazol-3-yl)benzamide 138

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(thiophen-2- yl)isoxazole-3-carboxamide 139

ethyl 1-(3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)phenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate 140

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H- imidazol-2-yl)benzamide 141

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)thiazole-4-carboxamide 142

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(1H-pyrazol-1-yl)benzamide 144

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(1,3-dimethyl-1H-pyrazol-4-yl)isoxazole-3-carboxamide 147

3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]imidazol-6-yl)benzamide148

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(5-methyl-1H- tetrazol-1-yl)benzamide 149

N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H-tetrazol-1- yl)benzamide 1B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3,5-dimethoxybenzamide 2B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(thiazol-2-yl)benzamide 3B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(3-methoxyphenyl)acetamide 4B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(furan-2-yl)nicotinamide 5B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-(1H-pyrazol-3-yl)benzamide 6B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(furan-2-yl)thiazole-4-carboxamide 7B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(dimethylamino)nicotinamide 8B

2-(3-chlorophenyl)-N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)acetamide 9B

4-amino-N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide 10B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(thiophene-3-carboxamido)-1,2,4-thiadiazole-3-carboxamide 11B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(thiophen-2-yl)thiazole-4-carboxamide 12B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide 13B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1-methyl-1H-pyrazole-4-carboxamide 14B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-thiomorpholinoisonicotinamide 15B

4-amino-N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-1H-pyrrole-2-carboxamide 16B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-2-(furan-3-yl)thiazole-4-carboxamide 17B

2-(3-chlorophenyl)-N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)thiazole-4-carboxamide 22B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-4-(1H-tetrazol-1-yl)benzamide 23B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-(thiophen-2-yl)nicotinamide 25B

N-(2,2-difluoro-5H- [1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-5-morpholinonicotinamide

or a physiologically functional derivative, solvate or salt thereof. 8.The compound according to claim 1 or a physiologically functionalderivative, solvate or salt thereof for use as a medicament.
 9. Thecompound according to claim 1 or a physiologically functionalderivative, solvate or salt thereof for use in the treatment orprevention of a medical condition selected from the group comprisingautoimmune inflammatory disorders, CNS disorders, sleeping disorders,and proliferative diseases including cancer.
 10. A pharmaceuticalcomposition comprising a compound according to claim 1 or aphysiologically functional derivative, solvate or salt thereof and oneor more pharmaceutically acceptable excipients.
 11. A method oftreatment or prevention of a medical condition selected from the groupcomprising autoimmune inflammatory disorders, CNS disorders, sleepingdisorders, and proliferative diseases including cancer, which comprisesthe administration of an effective amount of a compound according toclaim 1, or a physiologically functional derivative, solvate or saltthereof to a subject in need thereof.
 12. Use of a compound according toclaim 1, or a physiologically functional derivative, solvate or saltthereof in the manufacture of a medicament for the treatment orprevention of a medical condition selected from the group comprisingautoimmune inflammatory disorders, CNS disorders, sleeping disorders,and proliferative diseases including cancer.
 13. Process for thepreparation of a compound according to claim 1, wherein A is an —CONH—or —NHCO—, the process comprising the step of coupling a compound ofbelow Formula IV with a compound of below formula II;

wherein Y, L and X are as defined above, and wherein either R¹ is NH₂and R² is COOH or COOCl, or wherein R² is NH₂ and R¹ is COOH or COOCl.